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

Author:

Hayashi Yuki1ORCID,Takatori Sho2ORCID,Warsame Waleed Y3ORCID,Tomita Taisuke2ORCID,Fujisawa Takao1ORCID,Ichijo Hidenori1ORCID

Affiliation:

1. Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan

2. Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan

3. Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Abstract

AbstractEndoplasmic 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 phosphatidylinositol‐3‐phosphate (PI3P)‐binding protein 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 aberrant proteins by ER‐phagy, TOLLIP selectively clears aberrant cargos by coupling them with the PI3P‐dependent lysosomal trafficking without promoting bulk ER turnover. Moreover, TOLLIP depletion augments ER stress after ERAD inhibition, indicating that TOLLIP and ERAD cooperatively safeguard ER proteostasis. Our study identifies TOLLIP as a unique type of cargo‐specific adaptor dedicated to the clearance of aberrant ER cargos and provides insights into molecular mechanisms underlying lysosome‐mediated quality control of membrane proteins.

Funder

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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