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Thermobia domestica belongs to an ancient group of insects and has a remarkable ability to digest crystalline cellulose without microbial assistance. By investigating the digestive proteome of Thermobia, we have identified over 20 members of an uncharacterized family of lytic polysaccharide monooxygenases (LPMOs). We show that this LPMO family spans across several clades of the Tree of Life, is of ancient origin, and was recruited by early arthropods with possible roles in remodeling endogenous chitin scaffolds during development and metamorphosis. Based on our in-depth characterization of Thermobia’s LPMOs, we propose that diversification of these enzymes toward cellulose digestion might have endowed ancestral insects with an effective biochemical apparatus for biomass degradation, allowing the early colonization of land during the Paleozoic Era. The vital role of LPMOs in modern agricultural pests and disease vectors offers new opportunities to help tackle global challenges in food security and the control of infectious diseases., LPMOs catalyze the oxidative breakdown of polysaccharides, thereby facilitating biomass degradation. By analyzing the digestive proteome of firebrats, the authors here identify a yet uncharacterized LPMO family and provide phylogenetic, structural and biochemical insights into its origin and functions.

During cytokinesis, an actomyosin contractile ring drives the separation of thetwo daughter cells. A key molecule in this process is the inositol lipidPtdIns(4,5)P2, which recruits numerous factors to the equatorial region forcontractile ring assembly. Despite the importance of PtdIns(4,5)P2 in cytokinesis,the regulation of this lipid in cell division remains poorly understood. Here weidentify a role for IPIP27 in mediating cellular PtdIns(4,5)P2 homeostasis. IPIP27scaffolds the inositol phosphatase OCRL by coupling it to endocytic BAR domainproteins. Loss of IPIP27 causes accumulation of PtdIns(4,5)P2 on aberrantendomembrane vacuoles, mislocalization of the cytokinetic machinery, andextensive cortical membrane blebbing. This phenotype is observed in Drosophilaand human cells, and can result in cytokinesis failure. We have thereforeidentified IPIP27 as a key modulator of cellular PtdIns(4,5)P2 homeostasisrequired for normal cytokinesis. The results indicate that scaffolding of inositolphosphatase activity is critical for maintaining PtdIns(4,5)P2 homeostasis, andhighlight a critical role for this process in cell division.

Sphingolipids are found in abundance at synapses and have been implicated in regulation of synapse structure, function and degeneration. Their precise role in these processes, however, remains obscure. Serine Palmitoyl-transferase (SPT) is the first enzymatic step for synthesis of sphingolipids. Analysis of the Drosophila larval neuromuscular junction revealed mutations in the SPT enzyme subunit, lace/SPTLC2 resulted in deficits in synaptic structure and function. Although neuromuscular junction (NMJ) length is normal in lace mutants, the number of boutons per NMJ is reduced to ∼50% of the wild type number. Synaptic boutons in lace mutants are much larger but show little perturbation to the general ultrastructure. Electrophysiological analysis of lace mutant synapses revealed strong synaptic transmission coupled with predominance of depression over facilitation. The structural and functional phenotypes of lace mirrored aspects of Basigin (Bsg), a small Ig-domain adhesion molecule also known to regulate synaptic structure and function. Mutant combinations of lace and Bsg generated large synaptic boutons, while lace mutants showed abnormal accumulation of Bsg at synapses, suggesting that Bsg requires sphingolipid to regulate structure of the synapse. In support of this, we found Bsg to be enriched in lipid rafts. Our data points to a role for sphingolipids in the regulation and fine-tuning of synaptic structure and function while sphingolipid regulation of synaptic structure may be mediated via the activity of Bsg. This article is protected by copyright. All rights reserved.

Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. However, the pathological mechanisms driving neuronal atrophy in FTD remain poorly understood. Here we identify a conserved role for the novel pro-apoptotic protein plenty of SH3s (POSH)/SH3 domain containing ring finger 1 in mediating neuropathology in Drosophila and mammalian models of charged multivesicular body protein 2B (CHMP2BIntron5) associated FTD. Aberrant, AKT dependent, accumulation of POSH was observed throughout the nervous system of both Drosophila and mice expressing CHMP2BIntron5. Knockdown of POSH was shown to be neuroprotective and sufficient to alleviate aberrant neuronal morphology, behavioral deficits and premature-lethality in Drosophila models, as well as dendritic collapse and cell death in CHMP2BIntron5expressing rat primary neurons. POSH knockdown also ameliorated elevated markers of Jun N-terminal kinase and apoptotic cascades in both Drosophila and mammalian models. This study provides the first characterization of POSH as a potential component of an FTD neuropathology, identifying a novel apoptotic pathway with relevance to the FTD spectrum.

Reactive oxygen species (ROS) have long been studied as destructive agents in the context of nervous system ageing, disease and degeneration. Their roles as signalling molecules under normal physiological conditions is less well understood. Recent studies have provided ample evidence of ROS-regulating neuronal development and function, from the establishment of neuronal polarity to growth cone pathfinding; from the regulation of connectivity and synaptic transmission to the tuning of neuronal networks. Appreciation of the varied processes that are subject to regulation by ROS might help us understand how changes in ROS metabolism and buffering could progressively impact on neuronal networks with age and disease.