The role of EDEM3, Derlin-1 and Derlin-2 proteins in the ricin P250A cytotoxicity and its retrotranslocation from the endoplasmic reticulum to the cytosol

Abstract

ERAD-ER-associated degradation is a part of a protein quality control system operating in the endoplasmic reticulum (ER), which has an impact on process determining the proper functioning of all eukaryotic cells. Many of all newly synthesized proteins are produced in the ER. Some of them may fail to attain their native structure and have to be transported to the cytosol for proteasomal degradation (ERAD). The major group of chaperones which recognize terminally misfolded proteins is EDEM family (EDEM1, EDEM2, EDEM3) (Słomińska-Wojewódzka et al., 2006). The second type of proteins important in ERAD are Derlin family: Derlin-1, Derlin-2, and Derlin-3 which are thought to form a retrotranslocation channel (Oda et al., 2016). Ricin is a protein toxin that utilizes the ERAD pathway in its transport from the ER to the cytosol where it acts. It is heterodimeric holotoxin composed of an A-chain (RTA) connected to a cell binding lectin B-chain (RTB). RTA contains hydrophobic C-terminal region. Substitution of proline into alanine in position 250 (P250A) of this region alters the secondary structure of ricin and decreases its cytotoxicity (Słomińska-Wojewódzka & Sandvig, 2013).