Narendradev, N. D. | bioRxiv Science

bioRxiv2020

Endosomes facilitate mitochondrial clearance by enhancing Mfn2 degradation and subsequent Parkin recruitment

Mutations in ubiquitin ligase Parkin are associated with Parkinsons disease and defective mitophagy. Conceptually, Parkin-dependent mitophagy is classified into two phases; 1. Parkin recruits to and ubiquitinates mitochondrial proteins, 2. Formation of autophagosome membrane, sequestering mitochondria for degradation. Recently, endosomal machineries were reported to contribute to the later stage for membrane assembly. We report a role for endosomes in the events upstream of phase 1. We demonstrate that an endosomal ubiquitin ligase CARP2 associates with damaged mitochondria, and this association precedes that of Parkin. CARP2 interacts with Parkin, and stable recruitment of Parkin to damaged mitochondria was substantially reduced in CARP2 KO cells. Our study unravels a novel role of endosomes in modulating upstream pathways of Parkin-dependent mitophagy initiation.

cell biology↗

bioRxiv2019

Naturally Occurring Shorter and Tumor-associated Mutant RNF167 Variants Facilitates Lysosomal Exocytosis and Plasma Membrane Resealing

Lysosomal exocytosis and resealing of damaged plasma membrane play critical roles in physiological and pathological processes, including, restoration of cellular homeostasis and tumor invasion. However, to-date, only a few regulatory molecules of these biological processes have been identified. Moreover, no mutations in any of the known regulators of lysosomal exocytosis in primary tumors of patients have been characterized. Here we demonstrate that RNF167, a lysosomal associated ubiquitin ligase, negatively regulates lysosomal exocytosis by inducing perinuclear clustering of lysosomes. Importantly, we also characterized a set of novel natural mutations in RNF167, which are commonly found in diverse tumor types. We found that RNF167-K97N mutant, unlike the wild-type, localizes in the cytoplasm and does not promote perinuclear lysosomal clustering and that cells expressing RNF167-K97N exhibit dispersed lysosomes, increased exocytosis, and enhanced plasma membrane repair. Interestingly, these functional features of RNF167-K97N were shared with a naturally occurring short version of RNF167, i.e. isoform b. In brief, the results presented here reveal a novel role of RNF167 as well as its natural variants, RNF167-K97N and RNF167-b as an upstream regulator of lysosomal exocytosis and plasma membrane resealing which might play an important role in organelle dynamics or tumor progression or both.

cell biology↗