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

• Published in: The Journal of biological chemistry Vol. 288; no. 46; pp. 33462 - 33469
• Main Authors: Chen, Shu-Fen, Wu, Chun-Hu, Lee, Yen-Ming, Tam, Kabik, Tsai, Yi-Chen, Liou, Jun-Yang, Shyue, Song-Kun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.11.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptor Proteins, Vesicular Transport; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Animals; Caveolin; Caveolin 1 - genetics; Caveolin 1 - metabolism; Caveolin-1; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cyclooxygenase (COX) Pathway; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Derlin-1; ER-associated Degradation; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; p97; Protein Degradation; Protein Synthesis and Degradation; Protein Transport - physiology; Proteins - genetics; Proteins - metabolism; Proteolysis; Ubiquitination; Ubiquitination - physiology; Valosin Containing Protein; Caveolin-1; Ubiquitination; Caveolin; Derlin-1; Cyclooxygenase-2; Protein Degradation; Cyclooxygenase (COX) Pathway; ER-associated Degradation; p97
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.521799

Caveolin-1 (Cav-1) interacts with and mediates protein trafficking and various cellular functions. Derlin-1 is a candidate for the retrotranslocation channel of endoplasmic reticulum proteins. However, little is known about how Derlin-1 mediates glycosylated protein degradation. Here, we identified Cav-1 as a key player in Derlin-1- and p97-mediated cyclooxygenase 2 (COX-2) ubiquitination and degradation. Derlin-1 augmented the interaction of Cav-1 and COX-2 and mediated the degradation of COX-2 in a COX-2 C terminus-dependent manner. Suppression of Cav-1 decreased the ubiquitination of COX-2, and mutation of Asn-594 to Ala to disrupt N-glycosylation at the C terminus of COX-2 reduced the interaction of COX-2 with Cav-1 but not Derlin-1. Moreover, suppression of p97 increased the ubiquitination of COX-2 and up-regulated COX-2 but not COX-1. Cav-1 enhanced the interaction of p97 with Ufd1 and Derlin-1 and collaborated with p97 to interact with COX-2. Cav-1 may be a cofactor in the interaction of Derlin-1 and N-glycosylated COX-2 and may facilitate Derlin-1- and p97 complex-mediated COX-2 ubiquitination, retrotranslocation, and degradation. 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.