Massive ER protein disposal by reticulophagy receptors and selective disposal by TOLLIP

ABSTRACT

Proteostasis of the endoplasmic reticulum (ER) is maintained by coordinated action of two major catabolic pathways: proteasome-dependent ER-associated degradation (ERAD) and less characterized lysosomal pathways. Recent studies on ER-specific autophagy (termed “reticulophagy”) have highlighted the importance of lysosomes for ER proteostasis. Key to this process are proteins termed reticulophagy receptors that connect ER fragments and Atg8-family proteins, facilitating the lysosomal degradation of both native and aberrant ER proteins in a relatively nonselective manner. In contrast, our recent work identified TOLLIP as a novel type of cargo receptor specifically dedicated to the lysosomal degradation of aberrant ER membrane proteins. The clients of TOLLIP include an engineered model substrate, which mimics an ER-retained aberrant membrane protein, and motor neuron disease-linked misfolded mutants of VAPB and BSCL2/Seipin. TOLLIP acts as a receptor to connect these aberrant ER membrane proteins and phosphatidylinositol-3-phosphate (PtdIns3P) by recognizing the former through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain, and the latter through its C2 domain. These interactions enable PtdIns3P-dependent vesicular trafficking of aberrant membrane proteins to lysosomes without promoting reticulophagic turnover of bulk ER.

KEYWORDS:

• ER stress
• ER-phagy
• ERAD
• motor neuron disease
• reticulophagy
• TOLLIP

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the Japan Agency for Medical Research and Development for the Project for Elucidating and Controlling Mechanisms of Aging and Longevity [JP21gm5010001 to H.I.], by the Japan Society for the Promotion of Science for the Grants-in-Aid for Scientific Research [JP23K14143 to Y.H. and JP21H04760 to H.I.] and the Grant-in-Aid for Scientific Research on Innovative Areas [JP22H04636 to Y.H.], and by the Japan Science and Technology Agency for Moonshot R&D–MILLENNIA Program [JPMJMS2022-18 to H.I.].