Role of Derlin-1 Protein in Proteostasis Regulation of ATP-sensitive Potassium Channels

Abstract

Background: ATP-sensitive potassium (K ATP ) channels in the ␤-cell plasma membrane regulate insulin secretion. Results: Derlin-1 mediates degradation of K ATP channels in the endoplasmic reticulum, and manipulation of Derlin-1 levels affects biogenesis efficiency and surface expression of wild type and misfolded mutant channels. Conclusion: Derlin-1 plays a role in the homeostasis of K ATP channels. Significance: K ATP channel density can be modulated by changes in the expression of Derlin-1.

KATPChannels in the Cardiovascular System

“…There is evidence that K ATP channels can be degraded by the ERAD pathway. First, SUR1 and Kir6.2 have been demonstrated to form a complex with Derlin-1 and an associated p97 protein (858). Derlin-1 participates in the recognition of misfolded proteins, and it forms the retro-translocation channel, whereas p97 is an ATPase that links the misfolded proteins to ubiquitin ligases (656).…”

“…There is some evidence that under certain conditions K ATP channels can be diverted to a lysosomal degradation pathway since lysosomal inhibitors prevents protein kinase C (PKC)-induced degradation (538). It is likely, however, that constitutive degradation occurs via the proteasome since nonstimulated degradation is unaffected by the lysosomal inhibitor chloroquine and prevented by MG132, which is an inhibitor of the proteasome (788,858,891).…”

MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

“…The family of Der1 proteins has emerged as a vital component of the ERAD pathway [15]. DERL1 is a partner of the p97 ATPase complex and plays a key role in the mislocalization of the misfolded protein; it also integrates into the endoplasmic reticulum (ER) membrane to survey such protein aggregates [16, 17]. Recently, several studies have demonstrated that DERL1 contributes to carcinogenesis and tumor progression, and the upregulation of DERL1 expression promotes the development of colon cancer, esophageal cancer, and bladder cancer [18-20].…”

Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation

“…Therefore, studies are needed to identify this type of cancer cell, and the signaling molecules that are specifically involved in cancer progression. Derlin-1, a partner of the p97 ATPase complex, was initially reported to mediate the elimination of misfolded proteins from the endoplasmic reticulum (ER) and retrotranslocation of proteins into the cytosol [3][4][5]. Accumulating evidence has strongly implicated that Derlin-1 plays an important and multifaceted role in cancer progression [6][7][8][9][10][11][12].…”