Sang-Eun Park1,*, Jeong-Mok Kim1,*, Ok-Hee Seok1, Hanna Cho1, Brandon Wadas2, Seon-Young Kim3,4, Alexander Varshavsky2,†, Cheol-Sang Hwang1,†
1Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea. 2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
3Medical Genomics Research Center, KRIBB, Daejeon, South Korea.
4Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea.
†Corresponding author : Alexander Varshavsky, Cheol-Sang Hwang
* These authors contributed equally to this work.
Rgs2, a regulator of G proteins, lowers blood pressure by decreasing signaling through Gαq. Human patients expressing Met-Leu-Rgs2 (ML-Rgs2) or Met-Arg-Rgs2 (MR-Rgs2) are hypertensive relative to people expressing wild-type Met-Gln-Rgs2 (MQ-Rgs2). We found that wild-type MQ-Rgs2 and its mutant, MR-Rgs2, were destroyed by the Ac/N-end rule pathway, which recognizes Nα-terminally acetylated (Nt-acetylated) proteins. The shortest-lived mutant, ML-Rgs2, was targeted by both the Ac/N-end rule and Arg/N-end rule pathways. The latter pathway recognizes unacetylated N-terminal residues. Thus, the Nt-acetylated Ac-MX-Rgs2 (X = Arg, Gln, Leu) proteins are specific substrates of the mammalian Ac/N-end rule pathway. Furthermore, the Ac/N-degron of Ac-MQ-Rgs2 was conditional, and Teb4, an endoplasmic reticulum (ER) membrane-embedded ubiquitin ligase, was able to regulate G protein signaling by targeting Ac-MX-Rgs2 proteins for degradation through their Nα-terminal acetyl group.