Targeted Protein Degradation via Lysosomes

Authors

Rishi R Paudel
Dong Lu
Sandipan Roy Chowdhury
Erika Y Monroy
Jin Wang

Publication Date

2-7-2023

Journal

Biochemistry

DOI

10.1021/acs.biochem.2c00310

PMID

36130224

PMCID

PMC10245383

PubMedCentral® Posted Date

6-7-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Proteolysis, Proteasome Endopeptidase Complex, Ubiquitin, Autophagy, Membrane Proteins, Lysosomes

Abstract

In the scope of targeted protein degradation (TPD), proteolysis-targeting chimeras (PROTACs), leveraging the ubiquitin-proteasome system, have been extensively studied. However, they are limited to the degradation of soluble and membrane proteins, excluding the aggregated and extracellular proteins and dysfunctional organelles. As an alternative protein degradation pathway, lysosomes serve as a feasible tool for accessing these untouched proteins and/or organelles by proteosomes. Here, we focus on reviewing the emerging lysosome-mediated TPD, such as AUTAC, ATTEC, AUTOTAC, LYTAC, and MoDE-A. Intracellular targets, such as soluble and aggregated proteins and organelles, can be degraded via the autophagy-lysosome pathway. Extracellular targets, such as membrane proteins, and secreted extracellular proteins can be degraded via the endosome-lysosome pathway. In addition, we summarize the mechanism and regulation of autophagy, available methods and assays for monitoring the autophagy process, and the recently developed chemical probes for perturbing the autophagy pathways.