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.

中文翻译：

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TOLLIP 作为货物适配器促进异常 ER 膜蛋白的溶酶体降解


内质网（ER）蛋白质稳态由多种分解代谢途径维持。溶酶体通过 ER 吞噬清除整个 ER 部分，而蛋白酶体通过 ER 相关降解 (ERAD) 选择性清除错误折叠或多余的异常蛋白质。最近，溶酶体也与异常 ER 蛋白的选择性清除有关，但其分子基础仍不清楚。在这里，我们发现磷脂酰肌醇-3-磷酸（PI3P）结合蛋白 TOLLIP 促进异常膜蛋白的选择性溶酶体降解，包括 VAPB 和 Seipin 的人工底物和运动神经元致病突变体。 TOLLIP 通过其错误折叠感知固有无序区 (IDR) 和泛素结合 CUE 域来识别这些货物。与通过 ER 吞噬清除天然和异常蛋白质的 ER 吞噬受体相反，TOLLIP 通过将异常货物与 PI3P 依赖性溶酶体运输偶联来选择性清除异常货物，而不促进大量 ER 周转。此外，TOLLIP 耗尽会增加 ERAD 抑制后的 ER 应激，表明 TOLLIP 和 ERAD 共同保护 ER 蛋白质稳态。我们的研究将 TOLLIP 确定为一种独特类型的货物特异性接头，致力于清除异常的 ER 货物，并提供了对溶酶体介导的膜蛋白质量控制的分子机制的见解。