Degradation of Misfolded Secretory and Membrane Proteins and Associated Diseases

Abstract

Proper folding and targeting of proteins are pivotal for the functioning of cells. Misfolded secretory and membrane proteins are selected for degradation by the proteasome, a multisubunit cytosolic protease. This disposal process termed endoplasmic reticulum‐associated degradation (ERAD) includes recognition of misfolded proteins in the endoplasmic reticulum (ER), retrotranslocation of substrates from the ER to the cytosol, ubiquitylation of substrates by the ubiquitylation enzymes, targeting of substrates to the proteasome, preprocessing of the substrates for efficient proteasomal degradation and final cleavage of misfolded proteins by the proteasome. Malfunctioning of ERAD components or accumulation of misfolded substrates has been found to cause various human diseases ranging from neurodegenerative disorders to cancers. Understanding the mechanism underlying ERAD provides a critical stepping‐stone to design drugs and develop preventative and therapeutic strategies against these diseases. Key Concepts: Misfolded secretory and membrane proteins are degraded by ERAD. Malfunctioning of ERAD components or accumulation of misfolded substrates cause various human diseases. ERAD is composed of multiple steps including substrates recognition, retrotranslocation, ubiquitylation, targeting of substrates to the proteasome and the cleavage of substrates by the proteasome. ERAD substrates are recognised and sorted into different degradation pathways based on the location of the misfolded domain and the topology of the protein. The retrotranslocation of the substrates from the ER to the cytosol is mediated by undefined channel proteins. Retrotranslocated substrates are ubiquitylated by membrane associated E3 enzymes with the help from E1, E2 enzymes. Postubiquitylation processes in ERAD include substrate extraction from the ER membrane, substrate delivery to the proteasome, preprocessing of the substrates and proteasomal degradation.