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

Autor: Hayashi, Yuki, Takatori, Sho, Warsame, Waleed Y, Tomita, Taisuke, Fujisawa, Takao, Ichijo, Hidenori
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Zdroj: EMBO Journal; Dec2023, Vol. 42 Issue 23, p1-20, 20p
Abstrakt: 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 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. Synopsis: ER‐phagy receptors mediate bulk autophagic degradation of the endoplasmic reticulum (ER) by acting as ATG8‐binding adaptors. In contrast, the PI3P‐binding protein TOLLIP acts as a novel type of adaptor for selective lysosomal degradation of aberrant membrane proteins in the ER by sensing their misfolding and promoting their PI3P‐dependent traffic directly to the lysosome. TOLLIP promotes lysosomal degradation of aberrant membrane proteins in the ER through PI3P‐dependent trafficking.TOLLIP recognizes its clients through the misfolding‐sensing IDR and ubiquitin‐binding CUE domains.Unlike ER‐phagy receptors for bulk ER turnover, TOLLIP is dedicated to clearance of specific clients.TOLLIP clears motoneuron disease‐linked mutant membrane proteins and maintains ER proteostasis in conjunction with the ERAD pathway. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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