Search

Abstract Ultraviolet (UV) radiation, a component of sunlight, holds both advantageous anddetrimental effects on human health. While shorter wavelengths of UV radiationaid in melanin and vitamin D synthesis, longer wavelengths pose risks like skincancer and premature aging due to DNA damage. To combat such stress, cellsemploy various mechanisms, including the heat shock response (HSR). Activation of this response involves a highly regulated transcriptional processorchestrated by heat shock factors (HSFs). While HSF1 has been observed as a keytranscription factor for HSR, other HSFs are also found to be associated withdiverse cellular functions, including stress responses. Here, we discuss arecent study by Feng et al., published in Clinical and Translational Medicine, shedding light on the novel function of HSF4 in regulating inflammation and senescence following UV exposure. The researchers observed acomplex of HSF4 and the cofactor COIL (Coilin) at R‐loops–aberrant DNA‐RNAhybrid structures arising from UV‐induced DNA damage in human skin cells. Inthe study, they proposed the HSF4‐COIL complex at R‐loops as a potential therapeutic target to mitigate UV‐induced skin damage.

Changes in lipid metabolism are associated with aging and age-related diseases, including proteopathies. The endoplasmic reticulum (ER) is uniquely a major hub for protein and lipid synthesis, making its function essential for both protein and lipid homeostasis. However, it is less clear how lipid metabolism and protein quality may impact each other. Here, we identified let-767, a putative hydroxysteroid dehydrogenase in Caenorhabditis elegans, as an essential gene for both lipid and ER protein homeostasis. Knockdown of let-767 reduces lipid stores, alters ER morphology in a lipid-dependent manner, and blocks induction of the Unfolded Protein Response of the ER (UPRER). Interestingly, a global reduction in lipogenic pathways restores UPRER induction in animals with reduced let-767. Specifically, we find that supplementation of 3-oxoacyl, the predicted metabolite directly upstream of let-767, is sufficient to block induction of the UPRER. This study highlights a novel interaction through which changes in lipid metabolism can alter a cell’s response to protein-induced stress.

Actin cables affect lifespan by supporting movement and inheritance of fitter mitochondria to daughter cells in yeast. Here the authors show that branched-chain amino acid (BCAA) levels affect actin cable stability and a role for YKL075C/AAN1 in control of BCAA metabolism and actin cable stability and function.

Existing methods for multimeric protein complex quantification in single cells suffer from limited selectivity and sensitivity. Here the authors report Single-cell protein Interaction Fractionation Through Electrophoresis and immunoassay Readout (SIFTER) and use this to probe the effects of cellular stress.

Summary: The deleterious potential to generate oxidative stress is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and consequences of this remain unknown. Here, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that knockdown of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires ELT-3, NHR-49 and MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate. Activating SKN-1 results in increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 acts downstream of key catabolic pathways to influence physiology and stress resistance.

Organisms are constantly exposed to stress both from the external environment and internally within the cell. To maintain cellular homeostasis under different environmental and physiological conditions, cell have adapted various stress response signaling pathways, such as the heat shock response (HSR), unfolded protein responses of the mitochondria (UPRMT), and the unfolded protein response of the endoplasmic reticulum (UPRER). As cells grow older, all cellular stress responses have been shown to deteriorate, which is a major cause for the physiological consequences of aging and the development of numerous age-associated diseases. In contrast, elevated stress responses are often associated with lifespan extension and amelioration of degenerative diseases in different model organisms, including C. elegans. Activating cellular stress response pathways could be considered as an effective intervention to alleviate the burden of aging by restoring function of essential damage-clearing machinery, including the ubiquitin-proteosome system, chaperones, and autophagy. Here, we provide an overview of newly emerging concepts of these stress response pathways in healthy aging and longevity with a focus on the model organism, C. elegans.

Increasing the stability or dynamics of the actin cytoskeleton can extend lifespan in C. elegans and S. cerevisiae. Actin cables of budding yeast, bundles of actin filaments that mediate cargo transport, affect lifespan control through effects on mitochondrial quality control. Sir2p, the founding member of the Sirtuin family of lifespan regulators, also affects actin cable dynamics, assembly, and function in mitochondrial quality control. Here, we obtained evidence for novel interactions between Sir2p and Sum1p, a transcriptional repressor that was originally identified through mutations that genetically suppress sir2∆ phenotypes unrelated to lifespan. We find that deletion of SUM1 in wild-type cells results in increased mitochondrial function and actin cable abundance. Furthermore, deletion of SUM1 suppresses defects in actin cables and mitochondria of sir2∆ yeast, and extends the replicative lifespan and cellular health span of sir2∆ cells. Thus, Sum1p suppresses Sir2p function in control of specific aging determinants and lifespan in budding yeast.

Saccharomyces cerevisiae are widely used for imaging fluorescently tagged protein fusions. Fluorescent proteins can easily be inserted into yeast genes at their chromosomal locus, by homologous recombination, for expression of tagged proteins at endogenous levels. This is especially useful for incorporation of multiple fluorescent protein fusions into a single strain, which can be challenging in organisms where genetic manipulation is more complex. However, the availability of optimal fluorescent protein combinations for 3-color imaging is limited. Here, we have characterized a combination of fluorescent proteins, mTFP1/mCitrine/mCherry for multicolor live cell imaging in S. cerevisiae. This combination can be used with conventional blue dyes, such as DAPI, for potential four-color live cell imaging.