Cellular responses to misfolded proteins and protein aggregates

Abstract

Maintenance of the proteome is a major homeostatic task of the cell and disregulation of protein homeostasis can be deadly. The accumulation of different forms of misfolded protein can perturb protein homeostasis and cause extensive cell and tissue damage. The cell has various quality control systems to help prevent the accumulation of misfolded proteins and the complexity of the different mechanisms that have evolved is bewildering. The first order of business for all quality control systems is recognition of misfolded proteins, which is followed by a triage decision. In many cases, modular molecular chaperones function in different assemblies with degradatory or folding co-factors to direct a misfolded protein toward continued life or death. Herein, an overview of quality control mechanisms that triage soluble cytosolic proteins, protein aggregates, and ER-associated proteins is presented.

Fig. 1

The triage of misfolded proteins in cytosolic quality control. A denatured protein can spontaneously refold, aggregate, or be recognized by molecular chaperones, such as the Hsp40/Hsp70 co-chaperones. Hsp70 will attempt to refold the substrate protein by cycles of ATP hydrolysis or recruit E3-ubiquitin ligases, such as CHIP, to target the substrate for proteasomal degradation. Aggregated proteins will be cleared by autophagic processes.

Fig. 2

Misfolded proteins in the ER are subject to the ER-associated degradation (ERAD) pathway. Misfolded proteins are recognized by various ER factors, such as chaperones, and directed toward ER membrane E3 ubiquitin-ligases. The three main ligases identified are RMA1, HRD1, and TEB4. Each ligase is part of a complex with an E2 ubiquitin-conjugating enzyme and other factors. Substrate proteins are ubiquitylated, extracted into the cytoplasm via a p97 AAA + ATPase-dependent process, and degraded by the proteasome.