Safeguarding Lysosomal Homeostasis by DNAJC5/CSPα-Mediated Unconventional Protein Secretion and Endosomal Microautophagy

Juhyung Lee; Yue Xu; Yihong Ye

doi:10.3389/fcell.2022.906453

Safeguarding Lysosomal Homeostasis by DNAJC5/CSPα-Mediated Unconventional Protein Secretion and Endosomal Microautophagy

Front Cell Dev Biol. 2022 May 10:10:906453. doi: 10.3389/fcell.2022.906453. eCollection 2022.

Authors

Juhyung Lee¹, Yue Xu¹, Yihong Ye¹

Affiliation

¹ Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.

Abstract

Neuronal ceroid lipofuscinosis (NCL) is a collection of genetically inherited neurological disorders characterized by vision loss, seizure, brain death, and premature lethality. At the cellular level, a key pathologic hallmark of NCL is the build-up of autofluorescent storage materials (AFSM) in lysosomes of both neurons and non-neuronal cells. Molecular dissection of the genetic lesions underlying NCLs has shed significant insights into how disruption of lysosomal homeostasis may lead to lipofuscin accumulation and NCLs. Intriguingly, recent studies on DNAJC5/CSPα, a membrane associated HSC70 co-chaperone, have unexpectedly linked lipofuscin accumulation to two intimately coupled protein quality control processes at endolysosomes. This review discusses how deregulation of unconventional protein secretion and endosomal microautophagy (eMI) contributes to lipofuscin accumulation and neurodegeneration.

Keywords: DNAJC5/CSPα; ceroid lipofuscinosis neuronal; cysteine string protein; endosomal microautophagy; lysosome; misfolding-associated protein secretion (MAPS); protein quality control; unconventional protein secretion.

Publication types

Review