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Protein aggregates have a strong correlation with the pathogenesis of multiple human pathologies represented by neurodegenerative diseases. One type of selective autophagy, known as aggrephagy, can selectively degrade protein aggregates. A recent study from Ge lab reported the TRiC subunit CCT2 (chaperonin containing TCP1 subunit 2) as the first identified specific aggrephagy receptor in mammals. The switch of CCT2's role from a chaperonin to a specific aggrephagy receptor is achieved by CCT2 monomer formation. CCT2 functions independently of ubiquitin and the TRiC complex to facilitate the autophagic clearance of solid protein aggregates. This study provides the intriguing possibility that CCT2, as a specific aggrephagy receptor, might be an important target for the treatment of various diseases associated with protein aggregation.

STX17 (syntaxin 17) mediates autophagosome-lysosome fusion, and the translocation of STX17 to autophagosomes is characteristic of this process. STX17 arrives at autophagosomes when they are closed, stays there for approximately 10 min to promote fusion with lysosomes, and leaves when the autolysosomes are mature. However, the mechanism of this transient visit remains largely unknown. Here, we summarize the current knowledge about this phenomenon, including a recently discovered retrieval mechanism, and discuss remaining questions. Abbreviations: MAM: mitochondria-associated membrane; SNX: sorting nexin; STX17: syntaxin 17.

In the preceding months, the novel SARS-CoV-2 pandemic has devastated global communities. The need for safe and effective prophylactic and therapeutic treatments to combat COVID-19 – the human disease resulting from SARS-CoV-2 infection – is clear. Here, we present recent developments in the effort to combat COVID-19 and consider whether SARS-CoV-2 may potentially interact with the host autophagy pathway. Abbreviations: ACE2, angiotensin converting enzyme II; βCoV, betacoronavirus; COVID-19, Coronavirus Disease 2019; CQ, chloroquine; DMV, double-membrane vesicle; GI, gastrointestinal; HCQ, hydroxychloroquine; IL, interleukin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MEFs, mouse embryonic fibroblasts; MERS-CoV, Middle East respiratory syndrome coronavirus; MHV, murine hepatitis virus; PE, phosphatidylethanolamine; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane serine protease 2; TNF, tumor necrosis factor; WHO, World Health Organization

RB1CC1/FIP200 is a subunit of the ULK1 complex in more complex eukaryotes. This large polypeptide was proposed to be a functional homolog of the Atg17 and Atg11 scaffolding proteins in yeast. Previous studies showed that RB1CC1 can bind to various proteins of the macroautophagy/autophagy machinery, where the RB1CC1 Claw domain directly interacts with a short linear segment of its interactors. A mechanistic insight into how the small globular RB1CC1 Claw domain can interact with such an array of structurally variable proteins has been elusive. The recent study by Zhou et al., discussed here, yields structural data that not only provide a unifying mechanistic explanation of these interactions, but also reveals previously unknown RB1CC1 interactors and opens a new field for exploration of autophagy regulation. Abbreviations: FIR: FIP200-interacting region; LIR: LC3-interacting region; pS/p-S: phosphorylated serine

The autophagy receptor for selective reticulophagy, RETREG1/FAM134B is essential for ER maintenance, and its dysfunction is associated with neuronal disorders, vascular dementia, or viral infections. The protein consists of the reticulon-homology domain (RHD) that is flanked at the N- and C-termini by an intrinsically disordered protein region (IDPR), where the C terminal IDPR carries the indispensable LC3-interacting region (LIR) motif for the interaction with LC3. The RHD of RETREG1 is presumed to play a role in membrane remodeling, but the absence of a known 3D structure of this domain so far prevented researchers from gaining mechanistic insights into how the RETREG1 RHD curves membranes, and thereby facilities reticulophagy. The recent study by Bhaskara et al., which is described in this editor’s corner article, used molecular dynamics (MD) simulations to create a structural model of the RETREG1 RHD. MD simulations along with in vitro liposome remodeling experiments reveal how the RHD domain acts on the ER membrane and, in concert with the C terminal IDPR, executes the function of RETREG1 in selective reticulophagy. Abbreviations: ER, endoplasmic reticulum; IDPR, intrinsically disordered protein region; LIR, LC3-interacting region; MD, molecular dynamics; RHD, reticulon-homology domain; TM, transmembrane

Mitophagy, a type of selective autophagy targeting damaged or superfluous mitochondria, is critical to maintain cell homeostasis. Besides the well-characterized PRKN-dependent mitophagy, PRKN-independent mitophagy also plays significant physiological roles. In a recent study, researchers from Anne Simonsen’s lab discovered two lipid binding kinases, GAK and PRKCD, as positive regulators of PRKN-independent mitophagy. The researchers further investigated how these two proteins regulate mitophagy and demonstrated their roles in vivo. Focusing on the less known PRKN-independent mitophagy regulators, these findings shed light on understanding the mechanism of mitophagy and its relation to diseases.

When I invite authors to submit a punctum to Autophagy, my e-mail includes the following: "Note for international authors: I would like to point out that I personally edit all the puncta for accuracy, but also for English grammar and spelling. I make this point to all international authors as I do not want you to worry extensively about the writing. As a native English speaker, it is easy for me to make small changes of this nature." I do not claim to be an expert in English grammar; however, I am indeed a native English speaker, I read a lot, and I am even fond of using the dictionary (both hard copy and online). Also, I do a lot of editing. Thus, I thought I would share some common mistakes to help reduce the required edits for papers that are submitted to Autophagy.

The unique cellular organization and metabolic demands of neurons pose a challenge in the maintenance of neuronal homeostasis. A critical element in maintaining neuronal health and homeostasis is mitochondrial quality control via replacement and rejuvenation at the axon. Dysregulation of mitochondrial quality control mechanisms such as mitophagy has been implicated in neurodegenerative diseases including Parkinson disease and amyotrophic lateral sclerosis. To sustain mitophagy at the axon, a continuous supply of PINK1 is required; however, how do neurons maintain a steady supply of this protein at the distal axons? In the study highlighted here, Harbauer et al. show that axonal mitophagy is supported by local translation of Pink1 mRNA that is co-transported with mitochondria to the distal ends of the neuron. This neuronal-specific pathway provides a continuous supply of PINK1 to sustain mitophagy.

It would be quite convenient if every protein had one distinct function, one distinct role in just a single cellular process. In the field of macroautophagy/autophagy, however, we are increasingly finding that this is not the case; several autophagy proteins have two or more roles within the process of autophagy and many even "moonlight" as functional members of entirely different cellular processes. This is perhaps best exemplified by the Atg8-family proteins. These dynamic proteins have already been reported to serve several functions both within autophagy (membrane tethering, membrane fusion, binding to cargo receptors, binding to autophagy machinery) and beyond (LC3-associated phagocytosis, formation of EDEMosomes, immune signaling) but as Maruyama and colleagues suggest in their recent report, this list of functions may not yet be complete.

The Atg3 protein is highly homologous from yeast to human. Atg3 functions as an E2-like enzyme promoting conjugation of Atg8-family proteins to phosphatidylethanolamine (PE), a lipid molecule embedded in the growing phagophore membrane during stress-induced autophagy. Over the last decade, Atg3 became one of the most explored autophagy proteins, resulting in observations that provided specific insights into the structural mechanisms of its function. In this article, we describe a recent study by Ye et al. that reveals, using the human ATG3, how the membrane binding capability of the enzyme is tightly linked to its conjugation activity. We summarize the current knowledge on important mechanisms that involve protein-protein or protein-membrane interactions of Atg3 and that ultimately lead to efficient Atg8-PE conjugation.Abbreviations: AH: amphipathic helix; FR: flexible region; HR: handle region; NMR: nuclear magnetic resonance.

Time-restricted feeding (TRF) has recently gained interest as a potential anti-aging treatment for organisms from Drosophila to humans.(1–5) TRF restricts food intake to specific hours of the day. Because TRF controls the timing of feeding, not nutrient or caloric content, TRF has been hypothesized to depend on circadian-regulated functions; the underlying molecular mechanisms remain unclear. To exploit the genetic tools and well-characterized aging markers of Drosophila, we developed an intermittent TRF (iTRF) dietary regimen that robustly extended fly lifespan and delayed onset of aging markers in muscles and gut. We found that iTRF enhanced circadian-regulated transcription and that iTRF-mediated lifespan extension required both circadian regulation and autophagy, a conserved longevity pathway. Night-specific induction of autophagy was both necessary and sufficient to extend lifespan on ad lib diet and also prevented further iTRF-mediated lifespan extension. In contrast, day-specific induction of autophagy did not extend lifespan. Thus, these results identify circadian-regulated autophagy as a critical contributor to iTRF-mediated health benefits in Drosophila. Because both circadian regulation and autophagy are highly conserved processes in human aging, this work highlights the possibility that behavioral or pharmaceutical interventions stimulating circadian-regulated autophagy may provide people with similar health benefits such as delayed aging and lifespan extension.

In eukaryotes, ATG4/Atg4 is a critical regulator of macroautophagy/autophagy. The protease activity of Atg4/ATG4, involved in conjugation and deconjugation of Atg8-family proteins, was so far regarded as its sole functional contribution. However, the role of individual ATG4-family proteins during mammalian autophagy had previously not been examined in vivo. During their recent investigation, Nguyen et al. discovered a hitherto unexplored role for mammalian ATG4s during mitophagy - the recruitment of ATG9A-containing vesicles. Their article, highlighted here, discusses the finding, which uses a novel artificial intelligence (AI)-directed analysis technique for focused ion beam-scanning electron microscopy (FIB-SEM) imaging to demonstrate the role of ATG4s in promoting phagophore growth and establishing phagophore-ER contacts.

Although the aetiology of amyotrophic lateral sclerosis (ALS) remains poorly understood, impaired proteostasis is a common feature of different forms of ALS. Mutations in genes encoding ubiquilins, UBQLN2 and UBQLN4, cause familial ALS. The role of ubiquilins in proteasomal degradation is well established, but their role in autophagy-lysosomal clearance is poorly defined. Here, we describe a crosstalk between endoplasmic reticulum stress, mTOR signalling and autophagic flux in Drosophila and mammalian cells lacking ubiquilins. We found that loss of ubiquilins leads to endoplasmic reticulum stress, impairs mTORC1 activity, promotes autophagy and causes the demise of neurons. We show that ubiquilin mutants display defective autophagic flux due to reduced lysosome acidification. Ubiquilins are required to maintain proper levels of the V0a/V100 subunit of the vacuolar H+-ATPase and lysosomal pH. Feeding flies acidic nanoparticles alleviates defective autophagic flux in ubiquilin mutants. Hence, our studies reveal a conserved role for ubiquilins as regulators of autophagy by controlling vacuolar H+-ATPase activity and mTOR signalling.

VCP, a conserved ATPase, is involved in several cellular processes, and mutations in this protein are associated with various diseases. VCP also plays a role in autophagosome maturation. However, because a deficiency in autophagosome maturation presents a readily observable phenotype, other roles of VCP in autophagy regulation, in particular in the initial steps of autophagosome formation, may have been overlooked. In a recently published paper, using small-molecule inhibitors, Hill et al. showed that VCP regulates autophagy initiation through both stabilization of BECN1 and enhancement of phosphati-dylinositol 3-kinase (PtdIns3K) complex assembly.

It has been well established that Atg11 plays a critical role in selective macroautophagy/autophagy, but not in nonselective autophagy in the budding yeast Saccharomyces cerevisiae. However, its mammalian ortholog RB1CC1/FIP200 is indispensable for both types of autophagy, and the molecular mechanism behind its function is a mystery. Recently, Pan et al. showed that in the fission yeast Schizosaccharomyces pombe, Atg11 could also promote nonselective autophagy via activation of Atg1 kinase. These results prompt an interesting idea that Atg11 might have gained an additional ability to mediate nonselective autophagy through evolution.

Glucose deprivation induces macroautophagy/autophagy primarily through AMPK activation. However, little is known about the exact mechanism of this signaling. A recent study from Dr. David C. Rubinsztein's lab showed that ULK1 is activated by AMPK upon glucose starvation, resulting in the phosphorylation of the lipid kinase PIKFYVE on S1548. The activated PIKFYVE consequently enhances the formation of phosphatidylinositol-5-phosphate (PtdIns5P)-containing autophagosomes, and therefore drives autophagy upregulation. The novel discovery of how ULK1 regulates the non-canonical autophagy signaling (PtdIns5P-dependent autophagy), not only expands our knowledge of autophagy, but also sheds light on therapeutic strategies for curing human disorders, where glucose-induced starvation can play an important role.

Reticulophagy, a type of selective autophagy that specifically targets and degrades parts of the endoplasmic reticulum (ER) network (sheets or tubules), plays a crucial role in the responses to ER stress. The selectivity of the ER cargo recognition relies on the unique reticulophagy receptors, which tether and deliver cargos to phagophores, the precursors to autophagosomes. Various integral membrane proteins have been well characterized as reticulophagy receptors, including Atg39, Atg40, RETREG1/FAM134B, SEC62, RTN3L, CCPG1, TEX264, and ATL3, in both yeast and mammals in the past five years. In a recent paper, Zhao et al. discovered in fission yeast a novel reticulophagy receptor, Epr1, which bridges the ER and phagophore by binding to Atg8 and VAPs, a mechanism different from the aforementioned reticulophagy receptors.

Several studies have provided insight into the unique intracellular localization, dynamic trafficking and diverse repertoire of binding partners of Atg9/ATG9, but structural details of the protein have remained elusive. Guardia and colleagues now report the structure of human ATG9A to a resolution of 2.9 A, revealing, among other features, an elaborate system of tunnels permeating the ATG9A protein complex.

A key feature of macroautophagy (hereafter autophagy) is the formation of the phagophore, a double-membrane compartment sequestering cargos and finally maturing into a vesicle termed an autophagosome; however, where these membranes originate from is not clear. In a previous study, researchers from the Rubinsztein lab proposed a model in which the autophagosome can evolve from the RAB11A-positive recycling endosome. In their recent paper, they determine that DNM2 (dynamin 2) functions in scission of the recycling endosome, and the release of the autophagosome precursor. These findings explain how the centronuclear myopathy (CNM) mutation in DNM2 results in the accumulation of immature autophagic structures.

Classical macroautophagy/autophagy functions to maintain cell health during stressful conditions by targeting cytosolic components for degradation and recycling through the lysosomal pathway. In contrast, nondegradative secretory autophagy functions as an alternative autophagy mechanism to mediate extracellular secretion. A recent study published in Nature Cell Biology from the laboratory of Jayanta Debnath has identified components of the LC3-conjugation machinery as mediators in the selection of cargo for nonclassical secretion. Termed LC3-dependent extracellular vesicle loading and secretion (LDELS), this mechanism provides an additional link between secretory autophagy and the release of extracellular vesicles. ABBREVIATIONS: ATG, autophagy-related; BioID, proximity-dependent biotinylation; CM, conditioned medium; EV, extracellular vesicle; HNRNPK, heterogeneous nuclear ribonuclear protein K; ILVs, intralumenal vesicles; LDELS, LC3-dependent EV loading and secretion; LIR, LC3-interacting region; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MS, mass spectrometry; MVBs, multivesicular bodies; ncRNA, non-coding RNA; NSMAF/FAN, neutral sphingomyelinase activation associated factor; P-bodies, processing bodies; PE, phosphatidylethanolamine; RB1CC1/FIP200, RB1 inducible coiled-coil 1; RBP, RNA-binding protein; RNA-seq, RNA sequencing; SAFB, scaffold-attachment factor B; SILAC, stable isotope labeling of amino acids in cell culture; SMPD3/nSMase2, sphingomyelin phosphodiesterase 3; TEM, transmission electron microscopy; TMT, tandem mass tagging

Hypoxia is a physiological stress that frequently occurs in solid tissues. Autophagy, a ubiquitous degradation/recycling system in eukaryotic cells, renders cells tolerant to multiple stressors. However, the mechanisms underlying autophagy initiation upon hypoxia remains unclear. Here we show that protein arginine methyltransferase 5 (PRMT5) catalyzes symmetrical dimethylation of the autophagy initiation protein ULK1 at arginine 170 (R170me2s), a modification removed by lysine demethylase 5C (KDM5C). Despite unchanged PRMT5-mediated methylation, low oxygen levels decrease KDM5C activity and cause accumulation of ULK1 R170me2s. Dimethylation of ULK1 promotes autophosphorylation at T180, a prerequisite for ULK1 activation, subsequently causing phosphorylation of Atg13 and Beclin 1, autophagosome formation, mitochondrial clearance and reduced oxygen consumption. Further, expression of a ULK1 R170K mutant impaired cell proliferation under hypoxia. This study identifies an oxygen-sensitive methylation of ULK1 with an important role in hypoxic stress adaptation by promoting autophagy induction.

In a recent issue of this journal I attempted to explain the purpose of macroautophagy/autophagy to a non-specialist audience through the use of cartoons. In the present article, I am continuing this approach by considering the topic of autophagy regulation-why does the cell need to modulate the autophagic response, and what are the basic morphological mechanisms that can be used to attain different levels of autophagy activity?

Beginning with this issue, we present answers to practical questions regarding autophagy from the lay public.

The mammalian Atg8 family proteins are central drivers of autophagy and contain six members, classified into the LC3 and GABARAP subfamilies. Due to their high sequence similarity and consequent functional overlaps, it is difficult to delineate specific functions of Atg8 proteins in autophagy. Here we discover a super-strong GABARAP-selective inhibitory peptide harbored in 270/480 kDa ankyrin-G and a super-potent pan-Atg8 inhibitory peptide from 440 kDa ankyrin-B. Structural studies elucidate the mechanism governing the Atg8 binding potency and selectivity of the peptides, reveal a general Atg8-binding sequence motif, and allow development of a more GABARAP-selective inhibitory peptide. These peptides effectively blocked autophagy when expressed in cultured cells. Expression of these ankyrin-derived peptides in Caenorhabditis elegans also inhibited autophagy, causing accumulation of the p62 homolog SQST-1, delayed development and shortened life span. Thus, these genetically encodable autophagy inhibitory peptides can be used to occlude autophagy spatiotemporally in living animals.

In my role as an instructor I am constantly looking for ways to more effectively convey information to my audience, which is typically the students in my class. However, the same concerns apply to most of the people who attend a seminar. The approach you take to making the material easier to understand is likely to be influenced by the course you teach. That is, the same instructor may use different examples when teaching an upper division vs. a lower division course. I teach introductory biology, and my students may have little familiarity with cell biology, let alone autophagy. Accordingly, I have tried to consider how to illustrate the importance of autophagy in a way that can be comprehended by people who may not even be familiar with the term.

Macroautophagy/autophagy is a complex process that involves over 40 proteins in Saccharomyces cerevisiae. How these proteins are organized, and their activities orchestrated to facilitate an efficient autophagic mechanism remain elusive. Sawa-Makarsha et al. reconstitute the initial steps of autophagosome biogenesis during selective autophagy using autophagy factors purified from yeast. Their results show that Atg9 vesicles serve as platforms for the recruitment of the autophagy machinery, and establish membrane contact sites to initiate lipid transfer for autophagosome biogenesis. Abbreviations: GUV, giant unilamellar vesicles; PAS, phagophore assembly site; PL, proteolipisomes.

Selective autophagy is critical for the regulation of cellular homeostasis in organisms from yeast to humans. This process is a specific degradation pathway for a wide variety of substrates including unwanted cytosolic components, such as protein aggregates, damaged and/or superfluous organelles, and pathogens. However, it has been less clear as to whether a protein complex or substructure of an organelle can be targeted for removal by selective autophagy. One example of such a substrate is the nuclear pore complex (NPC), a large macromolecular assembly that is present throughout the nuclear envelope. Here, we highlight two recent studies that demonstrate for the first time that NPCs are targeted for vacuolar degradation through selective autophagy. ABBREVIATIONS: AIM: Atg8-interacting motif; NE: nuclear envelope; NPC: nuclear pore complex; Nup: nucleoporin; PMN/micronucleophagy: piecemeal microautophagy of the nucleus

There is a type of noncanonical autophagy, which is independent of ATG5 (autophagy related 5), also referred to as alternative autophagy. Both canonical and ATG5-independent alternative autophagy require the initiator ULK1 (unc-51 like kinase 1), but how ULK1 regulates these two types of autophagy differently remains unclear. A recent paper from Torii et al. demonstrates that phosphorylation of ULK1 at Ser746 by RIPK3 (receptor interacting serine/threonine kinase 3) is the key difference between these two types of autophagy; this phosphorylation is exclusively found during alternative autophagy.

AMPK is one of the main regulators of energy homeostasis in the cell, achieving this role in part by upregulating autophagy in times of nutrient deprivation. Previous reports have described several AMPK substrates involved in autophagy regulation; however, there are still undiscovered AMPK downstream effectors that could play an important role in autophagy. In a new article, Dohmen et al. discovered that the CCNY-CDK16 complex is a novel AMPK substrate involved in autophagy activation.

In 2013, Dr. Lora Hooper and colleagues described the induction of antibacterial macroautophagy/autophagy in intestinal epithelial cells as a cytoprotective host defense mechanism against invading Salmonella enterica serovar Typhimurium (S. Typhimurium). Canonical autophagy functions in a primarily degradative capacity to safeguard cells and ensure survival during stress conditions, including pathogen infection. In contrast, secretory autophagy has emerged as an alternative nondegradative mechanism for cellular trafficking and unconventional protein secretion. More recently, a study by Bel et al. from Dr. Hooper's lab describes how intestinal Paneth cells exploit the endoplasmic reticulum (ER) stress response to release antibacterial lysozyme through secretory autophagy in response to S. Typhimurium infection.

Drawing as a way of understanding things better/easier is in human nature, from textbook images through the models and graphical abstracts published in scientific papers to chalk talks during the academic job interview process. As a molecular cell biologist and geneticist, I always find it easier to show a microscopy image to engage a lay audience with the beauty of cells and explain the tremendous complexity one can extract from a single microphotograph. Unfortunately, I do not think that we as a science community are in general doing the best job at reaching out to the public and communicating what we do, why it is important and how beautiful and exciting our work is.

Based on my reading, and on my own experience, I have come to realize that people learn in different ways, and this can include the use of different media. This is one reason I have worked with various artists to portray the topic of autophagy through paintings, music and dance. Indeed, comments from members of the audience who have attended one of my seminars often suggest that a particular artistic approach ‘hit home’ and added meaning to them about the topic. In this issue of the journal I describe another such project—‘the-found-art vacuole’—that utilized the talents of an amazing watercolor painter, Scott Hartley. The object of Scott’s painting is the only artophagy composition that I have ‘made’—assembled is a more accurate word. Doing so was quite fun, but after examining many of the ‘antique’ items that form the ‘found-art vacuole’, I realized that it would be nice to have a painting that was done in exquisite detail. The requirement for detail immediately made me think of Scott, whose work I was familiar with from the Ann Arbor Art Fair. To quote a line from the Belleville News-Democrat describing Scott’s taking first place in an art competition, ‘He began by doing landscapes, and eventually found a different style for his work: the intricacies of urban architecture, of alleys and fire escapes in a city neighborhood.’ This does describe the nature of Scott’s work, but you have to see these paintings to appreciate the detail.

I am writing this editorial for two purposes. First, the plan is to start sending out invitations to prospective authors this month. If you have not heard from me by October 1, you would like to be...

In eukaryotes, TORC1/MTORC1 is a critical regulator of growth and proliferation. In response to nutrient abundance TORC1/MTORC1 favors anabolic processes and retards degradative ones. In S. cerevisiae, TORC1 is conventionally known to localize on the vacuolar membrane. In the course of their recent investigations, Hatakeyama et al. discovered a novel second site of TORC1 localization- the prevacuolar endosome. Their article, highlighted here, discusses the mechanism of TORC1 localization to the prevacuolar endosome and highlights a hitherto unappreciated mechanism by which 2 spatially separated pools of TORC1 execute the distinct functions of promoting anabolism and inhibiting degradation.

The actin regulator JMY creates filament networks that move membranes during autophagy. Hu and Mullins find that JMY is normally inhibited by interaction with the STRAP protein, but upon starvation, JMY is recruited away from STRAP and activated by LC3., During autophagy, actin filament networks move and remodel cellular membranes to form autophagosomes that enclose and metabolize cytoplasmic contents. Two actin regulators, WHAMM and JMY, participate in autophagosome formation, but the signals linking autophagy to actin assembly are poorly understood. We show that, in nonstarved cells, cytoplasmic JMY colocalizes with STRAP, a regulator of JMY’s nuclear functions, on nonmotile vesicles with no associated actin networks. Upon starvation, JMY shifts to motile, LC3-containing membranes that move on actin comet tails. LC3 enhances JMY’s de novo actin nucleation activity via a cryptic actin-binding sequence near JMY’s N terminus, and STRAP inhibits JMY’s ability to nucleate actin and activate the Arp2/3 complex. Cytoplasmic STRAP negatively regulates autophagy. Finally, we use purified proteins to reconstitute LC3- and JMY-dependent actin network formation on membranes and inhibition of network formation by STRAP. We conclude that LC3 and STRAP regulate JMY’s actin assembly activities in trans during autophagy.

Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.

Incidences of congenital syndrome associated with maternal zika virus (ZIKV) infection during pregnancy are well documented; however, the cellular and molecular mechanisms by which ZIKV infection causes these devastating fetal pathologies are still under active investigation. ZIKV is a member of the flavivirus family and is mainly transmitted to human hosts through Aedes mosquito vectors. However, in vivo models for the neurological tropism of the virus and the arthropod vector have been lacking. A recent study published in Cell Host & Microbe from Dr. Sara Cherry's lab investigates both of these key aspects of the ZIKV infectious life cycle. Liu et al. demonstrate how inflammatory activated Sting/dSTING-dependent antiviral macroautophagy/autophagy is sufficient to restrict ZIKV infection in the Drosophila melanogaster brain. Additionally, this study provides further evidence for the ancestral function of autophagy in protecting host cells from viral invaders. Abbreviations: AGO2: Argonaute 2; ATG: autophagy-related; Dcr-2: Dicer-2; DptA/Dipt: Diptericin A; Drs: Drosomycin; DCV: Drosophila C virus; IMD: immune-deficiency; qRT-PCR: quantitative real-time PCR; Rel/NF-κB: Relish; RNAi: RNA interference; ZIKV: zika virus.

A Google search for the combined terms "de Duve, autophagy, 1963" will reveal over 45,000 hits, most of them referring to the idea that the term autophagy was coined by the brilliant Christian de Duve on the sidelines of a symposium on lysosomes that took place in 1963. However, the first use of the term "autophagy" actually took place a century earlier.

Mitophagy is a conserved and highly regulated process of selective degradation crucial in maintaining normal cellular physiology. Genetic defects and cellular aberrations affecting mitophagy have been associated with the development of Parkinson disease. In their recently published article (highlighted in a punctum in this issue of the journal) Hsieh et al. present a putative mitophagy marker, which serves as a mechanistic link between sporadic and familial Parkinson disease.

Autophagy is a conserved catabolic homeostasis process central for cellular and organismal health. During autophagy, small single-membrane phagophores rapidly expand into large double-membrane autophagosomes to encapsulate diverse cargoes for degradation. It is thought that autophagic membranes are mainly derived from preformed organelle membranes. Instead, here we delineate a pathway that expands the phagophore membrane by localized phospholipid synthesis. Specifically, we find that the conserved acyl-CoA synthetase Faa1 accumulates on nucleated phagophores and locally activates fatty acids (FAs) required for phagophore elongation and autophagy. Strikingly, using isotopic FA tracing, we directly show that Faa1 channels activated FAs into the synthesis of phospholipids and promotes their assembly into autophagic membranes. Indeed, the first committed steps of de novo phospholipid synthesis at the ER, which forms stable contacts with nascent autophagosomes, are essential for autophagy. Together, our work illuminates how cells spatially tune synthesis and flux of phospholipids for autophagosome biogenesis during autophagy.

The lysosome degrades and recycles macromolecules, signals to the master growth regulator mTORC1 [mechanistic target of rapamycin (mTOR) complex 1], and is associated with human disease. We performed quantitative proteomic analyses of rapidly isolated lysosomes and found that nutrient levels and mTOR dynamically modulate the lysosomal proteome. Upon mTORC1 inhibition, NUFIP1 (nuclear fragile X mental retardation-interacting protein 1) redistributes from the nucleus to autophagosomes and lysosomes. Upon these conditions, NUFIP1 interacts with ribosomes and delivers them to autophagosomes by directly binding to microtubule-associated proteins 1A/1B light chain 3B (LC3B). The starvation-induced degradation of ribosomes via autophagy (ribophagy) depends on the capacity of NUFIP1 to bind LC3B and promotes cell survival. We propose that NUFIP1 is a receptor for the selective autophagy of ribosomes.

Recently, NIH has funded a center for autophagy research named the Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center (UNM HSC), with aspirations to promote autophagy research locally, nationally, and internationally. The center has 3 major missions: (i) to support junior faculty in their endeavors to develop investigations in this area and obtain independent funding; (ii) to develop and provide technological platforms to advance autophagy research with emphasis on cellular approaches for high quality reproducible research; and (iii) to foster international collaborations through the formation of an International Council of Affiliate Members and through hosting national and international workshops and symposia. Scientifically, the AIM center is focused on autophagy and its intersections with other processes, with emphasis on both fundamental discoveries and applied translational research.

Macroautophagy/autophagy plays a dual role in cancer depending on the stage of tumorigenesis. Autophagy prevents tumor initiation by suppressing chronic tissue damage, inflammation, accumulation of damaged organelles and genome instability. Autophagy can also sustain tumor metabolism and provide nutrients for tumor growth and survival via nutrient recycling. Moreover, autophagy is required for benign tumors to progress to malignant tumors. Emerging evidence indicates that autophagy or mitophagy can inactivate tumor suppressors such as TP53/TRP53/p53 to promote tumor progression once carcinogenesis has been initiated.

Macroautophagy/autophagy is a fundamental intracellular homeostatic process that is of interest both for its basic biology and for its effect on human physiology in a wide spectrum of conditions and diseases. Autophagy was first appreciated primarily as a metabolic and cytoplasmic quality control process, but in the past decade its role in immunity has been steadily growing. The connections between these aspects beckon explorations of the network and connections that exist between metabolism, quality control, and inflammation and immunity processes, which are so key to many human diseases including neurodegeneration, obesity and diabetes, chronic inflammatory conditions, cancer, infection, and aging. The purpose of this issue is to stimulate further the burgeoning studies of the intersections between autophagy and inflammation, and the inevitable overlaps with metabolic and quality control functions of autophagy.

Xenophagy, a unique type of selective macroautophagy/autophagy, targets invading pathogens as part of the host immune response. In order to survive within the host, bacteria have established various self-defense mechanisms. In a recent paper from Feng Shao’s lab, the Salmonella effector protein SopF has been demonstrated to block xenophagy by interrupting the vacuolar type H(+)-translocating (v-) ATPase-ATG16L1 axis, which is important for antibacterial autophagy initiation. SopF can specifically ADP-ribosylate Gln124 on ATP6V0C, a v-ATPase component, thus influencing recruitment of ATG16L1 onto the bacteria-containing vacuole within the host cytosol. Abbreviations: ATG: autophagy-related; S. Typhimurium: Salmonella enterica serovar Typhimurium; T3SS: type III secretion system

ULK1 and ATG13 assemble with RB1CC1/FIP200 and ATG101 to form a macroautophagy (hereafter autophagy) induction (ULK1) complex in higher eukaryotes. The yeast counterpart, the Atg1 complex, is comprised of Atg1 and Atg13 (ULK1 and ATG13 homologs), Atg17 (a proposed functional homolog of RB1CC1), and either the Atg101 subunit (in Schizosaccharomyces pombe) or the Atg29-Atg31 heterodimer (in Saccharomyces cerevisiae). With mutual exclusivity of, and no detectable homology between, the Atg29-Atg31 dimer and Atg101, knowledge about the roles of these proteins in autophagy induction is an important piece in the puzzle of understanding the molecular mechanism of autophagy initiation. A recent study reporting the structure of the S. pombe homolog Atg101 bound to the Atg13HORMA domain is a notable contribution to this knowledge (see the punctum in this issue of the journal).

Macroautophagy/autophagy is primarily a degradative pathway that clears malfunctioning cellular components in response to various types of stress. Recent studies have indicated that autophagy also plays an important role in maintaining genome stability. Loss of autophagy is associated with increased damage to DNA, inappropriate amplification of genomic regions and abnormal chromosome number. In a recent paper by Wang et al. the authors uncover a mechanism through which autophagy regulates the ubiquitination of chromatin. In particular, the autophagy receptor and substrate SQSTM1/p62 inhibits the E3 ligase RNF168-dependent ubiquitination of histone in response to DNA double-strand breaks. Dysregulation of this process leads to a reduced ability to repair DNA and a corresponding increase in the sensitivity of cells to radiation-induced damage.

When it comes to cancer initiation and progression, macroautophagy/autophagy seemingly acts in a contradictory fashion, serving either as a suppressive factor that functions to protect against tumor formation or as a support mechanism that sustains the disease itself through its cytoprotective functions. In tumor suppression, autophagy assists by restricting oxidative stress and curbing genomic instability that could possibly cause oncogenic mutations. However, in certain circumstances, autophagy can also promote cancer by providing nourishment and by limiting stress-response pathways, leading to cancer cell survival and rapid proliferation. Thus, autophagy's role in oncogenesis is highly context-dependent and varies from one cancer type to another. As a consequence, identifying the mechanisms that alter and rewire autophagic regulation and flux is extremely crucial to target autophagy as a possible avenue for anticancer treatment. In a recent study, Qian et al. endeavored to identify one such key regulatory pathway in hypoxia- and glutamine deprivation-induced autophagy in tumorigenic cells. In this pathway, phosphatidylinositol 3-phosphate (PtdIns3P) production by the class III phosphatidylinositol 3-kinase (PtdIns3K) complex is greatly improved through a cascade of posttranslational modifications that culminates in the phosphorylation of the scaffolding protein BECN1 by the glycolytic pathway kinase PGK1.

Mechanisms of selective autophagy of the ER, known as ER-phagy, require molecular delineation, particularly in vivo. It is unclear how these events control ER proteostasis and cellular health. Here, we identify cell-cycle progression gene 1 (CCPG1), an ER-resident protein with no known physiological role, as a non-canonical cargo receptor that directly binds to core autophagy proteins via an LIR motif to mammalian ATG8 proteins and, independently and via a discrete motif, to FIP200. These interactions facilitate ER-phagy. The CCPG1 gene is inducible by the unfolded protein response and thus directly links ER stress to ER-phagy. In vivo, CCPG1 protects against ER luminal protein aggregation and consequent unfolded protein response hyperactivation and tissue injury of the exocrine pancreas. Thus, via identification of this autophagy protein, we describe an unexpected molecular mechanism of ER-phagy and provide evidence that this may be physiologically relevant in ER luminal proteostasis.