Reprogramming endo-lysosomal proteostasis disease stress by UBR1- and arginylation-driven endophagy and autophagy protein quality control

Abstract

Protein quality control (PQC) is a conformational surveillance system critical to maintaining native protein composition in the cell. However, PQC mechanisms at the endo-lysosomal pathway especially toward membrane proteins and during cumulative endo-lysosomal stress are incompletely understood. We recently identified the ubiquitin ligase UBR1 as a PQC E3 ubiquitin-ligase for endosomal and/or cytosolic Ca2+-increase mediated proteostasis disease stress. As a consequence of the endosomal stress and/or cytosolic Ca2+-increase, the QC pathway using selective endosomal autophagy (endophagy) and autophagy was activated for ubiquitinated and arginylated UBR1-SQSTM1/p62 cargoes. In turn, the loss of UBR1, arginylation or both evoke endo-lysosomal pathway stress. Our data suggest that UBR1 with arginylation-dependent endophagy and autophagy is required during proteostasis perturbations and highlight the importance of UBR1 in stress-induced autophagy QC with implications for various human diseases.

Keywords

• autophagosome
• endosome
• lysosome
• proteostasis stress
• regeneration
• sqstm1/p62
• ubiquitination