Abstract
Adenylyl cyclases (ACs) generate cAMP, a second messenger of utmost importance that regulates a vast array of biological processes in all kingdoms of life. However, almost nothing is known about how AC activity is regulated through protein degradation mediated by ubiquitination or other mechanisms. Here, we show that transcriptional regulator interacting with the PHD-bromodomain 1 (TRIP-Br1, Sertad1), a newly identified protein with poorly characterized functions, acts as an adaptor that bridges the interaction of multiple AC isoforms with X-linked inhibitor of apoptosis protein (XIAP), a RING-domain E3 ubiquitin ligase. XIAP ubiquitinates a highly conserved Lys residue in AC isoforms and thereby accelerates the endocytosis and degradation of multiple AC isoforms in human cell lines and mice. XIAP/TRIP-Br1-mediated degradation of ACs forms part of a negative-feedback loop that controls the homeostasis of cAMP signaling in mice. Our findings reveal a previously unrecognized mechanism for degrading multiple AC isoforms and modulating the homeostasis of cAMP signaling.
Highlights
CAMP, the first second messenger discovered by Earl Sutherland in 1957, plays a crucial role in regulating a vast array of biological processes in all kingdoms of life by targeting PKA, Epac, cyclic nucleotide-gated ion channels, and Popdc proteins. cAMP is produced from ATP by adenylyl cyclases (ACs)
Our preliminary data indicated that exogenous TRIP-Br1 may interact with AC1
Further mapping showed that catalytic domain 1b (C1b; aa 494–612) of AC1 is sufficient for binding TRIP-Br1 (Figure 1c and e)
Summary
CAMP, the first second messenger discovered by Earl Sutherland in 1957, plays a crucial role in regulating a vast array of biological processes in all kingdoms of life by targeting PKA, Epac, cyclic nucleotide-gated ion channels, and Popdc proteins. cAMP is produced from ATP by adenylyl cyclases (ACs). CAMP is produced from ATP by adenylyl cyclases (ACs). Based on their structural and functional similarities, 9 transmembrane ACs (tmACs) in mammals are classified into four groups (Patel et al, 2001). Almost all previous studies on ACs have focused on the regulation of their activities per se, and despite the pivotal role of ACs in cAMP signaling, next to nothing is known about the degradation of cell-surface ACs mediated by ubiquitination and/or other mechanisms that acutely and finely tune the signaling potential of cell-surface membrane proteins in response to environmental cues (Piper and Luzio, 2007; MacGurn et al, 2012)
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