TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins

ABSTRACT: Endoplasmic reticulum (ER) proteostasis is maintained by various catabolic pathways. Lysosomes clear entire ER portions by ER-phagy, while proteasomes selectively clear misfolded or surplus aberrant proteins by ER-associated degradation (ERAD). Recently, lysosomes have also been implicated in the selective clearance of aberrant ER proteins, but the molecular basis remains unclear. Here we show that the autophagy receptor TOLLIP promotes selective lysosomal degradation of aberrant membrane proteins, including an artificial substrate and motoneuron disease-causing mutants of VAPB and Seipin. These cargos are recognized by TOLLIP through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain. In contrast to ER-phagy receptors, which clear both native and

SUBMITTER: Dr. Yuki Hayashi 

PROVIDER: S-SCDT-10_15252-EMBJ_2023114272 | biostudies-other |

REPOSITORIES: biostudies-other