Downregulation of cyclooxygenase-2 by the carboxyl-tail of the Angiotensin II type 1 receptor [Signal Transduction]

September 17th, 2014 by Sood, R., Minzel, W., Rimon, G., Tal, S., Barki-Harrington, L.

The enzyme cyclooxygenase-2 (COX-2) plays an important role in the kidney by upregulating the production of the vasoconstrictor hormone angiotensin II (AngII), which in turn downregulates COX-2 expression via activation of the angiotensin II type 1 receptor (AT1) receptor. Chemical inhibition of the catalytic activity of COX-2 is a well-established strategy for treating inflammation but little is known of cellular mechanisms that dispose of the protein itself. Here we show that in addition to its indirect negative feedback on COX-2, AT1 also downregulates the expression of COX-2 via a pathway that does not involve G-protein or β-arrestin-dependent signaling cascades. Instead, AT1 enhances the ubiquitination and subsequent degradation of the enzyme in the proteasome through elements in its cytosolic carboxyl tail (CT). We find that a mutant receptor that lacks the last 35 amino acids of its CT (Δ324) is devoid of its ability to reduce COX-2, and that expression of the CT sequence alone is sufficient to downregulate COX-2. Collectively these results propose a new role for AT1 in regulating COX-2 expression in a mechanism that deviates from its canonical signaling pathways. Downregulation of COX-2 by a short peptide that originates from AT1 may present as a basis for novel therapeutic means of eliminating excess COX-2 protein.