Biology subjects

Modi, J.

Publications and source records attributed to Modi, J..

2 recordsLinked to original sources

bioRxiv2023

A Conserved Requirement for RME-8/DNAJC13 in Neuronal Autolysosome Reformation

Autophagosomes fuse with lysosomes, forming autolysosomes that degrade engulfed cargo. To maintain lysosomal capacity, autolysosome reformation (ALR) must regenerate lysosomes from autolysosomes using a membrane tubule-based process. Maintaining lysosomal capacity is required to maintain proteostasis and cellular health, especially in neurons where lysosomal dysfunction has been repeatedly implicated in neurodegenerative disease. Cell biological studies have linked the DNA-J domain Hsc70 co-chaperone RME-8/DNAJC13 to endosomal coat protein regulation, while human genetics studies have linked RME-8/DNAJC13 to neurological disease, including Parkinsonism and Essential Tremor. We report new analysis of the requirements for the RME-8/DNAJC13 protein in neurons, focusing on C. elegans mechanosensory neurons in the intact animal, and in primary mouse cortical neurons in culture. We find that loss of RME-8/DNAJC13 in both systems results in accumulation of grossly elongated autolysosomal tubules. Further C. elegans analysis revealed a similar autolysosome tubule accumulation defect in mutants known to be required for ALR in mammals, including bec-1/beclin and vps-15/PIK3R4/p150 that regulate type-III PI3-kinase VPS-34, and dyn-1/dynamin that severs ALR tubules. Clathrin is also an important ALR regulator implicated in autolysosome tubule formation and release. In C. elegans we found that loss of RME-8 causes severe depletion of clathrin from neuronal autolysosomes, a phenotype shared with bec-1 and vps-15 mutants. We conclude that RME-8/DNAJC13 plays a conserved but previously unrecognized role in autolysosome reformation, likely affecting ALR tubule initiation and/or severing. Additionally, in both systems, we found that loss of RME-8/DNAJC13 appeared to reduce autophagic flux, suggesting feedback regulation from ALR to autophagy. Our results connecting RME-8/DNAJC13 to ALR and autophagy provide a potential mechanism by which RME-8/DNAJC13 could influence neuronal health and the progression of neurodegenerative disease.

cell biology↗

bioRxiv2019

Staphylococcus pasteuri isolates (Spvs) from human atherosclerotic plaques mediate virulence, intracellular resistance and transendothelial invasion of macrophages: A mechanistic paradigm for microbial pathogenicity in atherosclerosis

Atherosclerotic cardiovascular disease, a chronic inflammatory condition of multifactorial etiology, is the leading cause of death worldwide. The concept of bacterial persistence has been proposed as one of several contributing factors to this disease. We hypothesized that the infectious agent(s) found at the site of the atheroma may be dormant but perpetuate virulence in response to host defense and other physiological triggers. In this study, we sought to identify the source of persistent infection in human atherosclerotic plaque and define how pathogen virulence and host defenses mediate plaque vulnerability. Whole genome sequencing (WGS) was used to identify bacteria from pure cultures obtained from atherosclerotic tissues of living subjects diagnosed with more than 70% occlusion of the carotid artery undergoing carotid endarterectomy (CE). WGS identified the predominant species as S. pasteuri (Spv) in all CE isolates grown in pure culture except one isolate which was identified as B. licheniformis. All S. pasteuri isolates (Spvs) were found to contain genes for widespread virulence, invasion, and intracellular resistance. As macrophages (M{varphi}s) play a decisive role at all stages of this disease we treated mouse M{varphi}s (RAW 264.7) with Spvs. While all Spvs tested demonstrated their ability to survive phagocytosis, the highly virulent Spvs also activated M{varphi}s and induced trans-endothelial cell migration of these cells which was mediated via the CC chemokine CCL1 and its receptor CCR8. In conclusion, we show that Spvs are found in CE plaques, have the capacity to survive phagocytosis and induce the transmigration of M{varphi}s across an endothelial barrier in a CCL1-CCR8 dependent process. These findings highlight the significance of carotid vessels as a reservoir for S. pasteuri, a pathogen found in products used routinely in human consumption; this may explain how microbial pathogenicity modulates plaque vulnerability in atherosclerosis.

pathology↗