Caveolin-1 Interacts with Derlin-1 and Promotes Ubiquitination and Degradation of Cyclooxygenase-2 via Collaboration with p97 Complex

Abstract

Background: Caveolin-1 assists in COX-2 degradation through the proteasome pathway. Results: Caveolin-1 enhances interactions among COX-2, Derlin-1, and the p97-Ufd1 complex and assists in COX-2 retrotranslocation and ubiquitination. Conclusion: Caveolin-1 is a cofactor facilitating COX-2 degradation via a Derlin-1-p97 pathway. Significance: Results represent a novel model for Derlin-1-mediated N-glycosylated protein degradation facilitated by caveolin-1.

Down-regulation of Cyclooxygenase-2 by the Carboxyl Tail of the Angiotensin II Type 1 Receptor

“…In the absence of its major substrate AA, COX-2 undergoes continuous turnover by shuttling from the endoplasmic reticulum to the cytosol via the ER-associated degradation (ERAD) pathway, where it is subsequently degraded by the proteasome (9). Degradation of COX-2 in the proteasome is preceded by its polyubiquitination (10), and was recently shown to be facilitated by caveolin-1 (11) and also through its interaction with the GPCRs, prostaglandin E 1 (EP 1 ), and ␤ 1 adrenergic (␤ 1 AR) receptors (12,13). Here we set to explore whether, in addition to the known negative feedback loop between angiotensin II and COX-2, there is an additional mechanism for down-regulating COX-2 expression by AT 1 , and to identify the domains of the receptor that mediate this effect.…”

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].…”

A Cyclooxygenase-2-dependent Prostaglandin E2 Biosynthetic System in the Golgi Apparatus

“…Finally, in events involving EDEM, ERp57, OS-9, XTP3-B, and the HRD1-SEL1L ubiquitin ligase complex (39,44), a trimmed and unfolded COX-2 is translocated to the cytosol for ubiquitination and proteasomal degradation (25,28,29,32,35). The slow glycosylation observed with KDEL huCOX-2 suggests that the rate-limiting step in ERAD of COX-2 is post-translational glycosylation of Asn-594 in the ER.…”

“…We have reported that properly folded COX-2 can be degraded via two distinct pathways including AA turnover-dependent degradation and constitutive degradation involving the ER-associated degradation (ERAD) pathway (29,30). Others have shown that COX-2 can be ubiquitinated and degraded through the 26 S proteasome (32,35). ERAD involves a series of related but different events that include detecting misfolded proteins bound for degradation, translocating these proteins into the cytosol, and degrading the proteins via the 26 S proteasome (for recent reviews see, Refs.…”

“…1A). N-Glycosylation of Asn-594 within the degron occurs post-translationally and is central to its ERAD (29,30,35). An N594A mutation in COX-2 blocks enzyme degradation.…”