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

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.