Abstract
Aberrant metabolic forms of the prion protein (PrP), membrane-associated CtmPrP and cytosolic (cyPrP) interact with the cytosolic ubiquitin E3 ligase, Mahogunin Ring Finger-1 (MGRN1) and affect lysosomes. MGRN1 also interacts with and ubiquitinates TSG101, an ESCRT-I protein, involved in endocytosis. We report that MGRN1 modulates macroautophagy. In cultured cells, functional depletion of MGRN1 or overexpression of CtmPrP and cyPrP blocks autophagosome–lysosome fusion, alleviates the autophagic flux and its degradative competence. Concurrently, the degradation of cargo from the endo-lysosomal pathway is also affected. This is significant because catalytic inactivation of MGRN1 alleviates fusion of lysosomes with either autophagosomes (via amphisomes) or late endosomes (either direct or mediated through amphisomes), without drastically perturbing maturation of late endosomes, generation of amphisomes or lysosomal proteolytic activity. The compromised lysosomal fusion events are rescued by overexpression of TSG101 and/or its monoubiquitination in the presence of MGRN1. Thus, for the first time we elucidate that MGRN1 simultaneously modulates both autophagy and heterophagy via ubiquitin-mediated post-translational modification of TSG101.
Highlights
Perturbations in autophagy-related protein (ATG) genes, Atg[7] and Atg[5] lead to developmental defects during organogenesis[3,4] or even neonatal death.[5]
This study elucidates the mechanism by which MGRN1 regulates lysosomal degradation by simultaneously affecting autophagy and heterophagy
In cell lines and primary cells, functional inactivation of MGRN1 led to an increase in the number and size of LC3 positive vesicles, indicating altered autophagy
Summary
Perturbations in autophagy-related protein (ATG) genes, Atg[7] and Atg[5] lead to developmental defects during organogenesis[3,4] or even neonatal death.[5]. Many other neurodegenerative diseases like Parkinson’s disease, Niemann–Pick type C disease, frontotemporal dementia (FTD) and amyotropic lateral sclerois (ALS) are referred as ‘lysosomal diseases’ These are all associated with dysfunction of the ESCRT (endosomal sorting complex required for transport) machinery, comprising a pathway of five distinct complexes (ESCRTs -0, -I, -II and -III, and Vps4), which recognize and sort ubiquitinated cargo through an exquisite division of labor.[10] Depletion or mutations in the molecular players of the ESCRT complexes severely affects the structure and function of endo-lysosomal compartments.[11,12,13,14] These proteins facilitate autophagy by affecting fusion events involving lysosomes, endosomes and autophagosomes.[15,16,17,18,19,20]. MGRN1 can modulate clearance of cargo at the lysosomes by regulating vesicular fusion events
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