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Degradation of Serotonin N-Acetyltransferase, a Circadian Regulator, by the N-end Rule Pathway

Wadas, Brandon and Borjigin, Jimo and Huang, Zheping and Oh, Jang-Hyun and Hwang, Cheol-Sang and Varshavsky, Alexander (2016) Degradation of Serotonin N-Acetyltransferase, a Circadian Regulator, by the N-end Rule Pathway. Journal of Biological Chemistry, 291 (33). pp. 17178-17196. ISSN 0021-9258. PMCID PMC5016120. doi:10.1074/jbc.M116.734640.

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Serotonin N-acetyltransferase (AANAT) converts serotonin to N-acetylserotonin (NAS), a distinct biological regulator and the immediate precursor of melatonin, a circulating hormone that influences circadian processes, including sleep. N-terminal sequences of AANAT enzymes vary among vertebrates. Mechanisms that regulate the levels of AANAT are incompletely understood. Previous findings were consistent with the possibility that AANAT may be controlled through its degradation by the N-end rule pathway. By expressing the rat and human AANATs and their mutants not only in mammalian cells but also in the yeast Saccharomyces cerevisiae, and by taking advantage of yeast genetics, we show here that two complementary forms of rat AANAT are targeted for degradation by two complementary branches of the N-end rule pathway. Specifically, the Nα terminally acetylated (Nt-acetylated) Ac-AANAT is destroyed through the recognition of its Nt acetylated N terminal Met residue by the Ac/N-end rule pathway, whereas the non Nt acetylated AANAT is targeted by the Arg/N end rule pathway, which recognizes the unacetylated N-terminal Met-Leu sequence of rat AANAT. We also show, by constructing lysine to arginine mutants of rat AANAT, that its degradation is mediated by polyubiquitylation of its Lys residue(s). Human AANAT, whose N-terminal sequence differs from that of rodent AANATs, is longer lived than its rat counterpart, and appears to be refractory to degradation by the N-end rule pathway. Together, these and related results indicate both a major involvement of the N-end rule pathway in the control of rodent AANATs and substantial differences in the regulation of rodent and human AANATs that stem from differences in their N terminal sequences.

Item Type:Article
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URLURL TypeDescription CentralArticle
Wadas, Brandon0000-0003-2796-2384
Oh, Jang-Hyun0000-0002-2053-7468
Hwang, Cheol-Sang0000-0002-0105-5957
Varshavsky, Alexander0000-0002-4011-258X
Additional Information:© 2016 The American Society for Biochemistry and Molecular Biology. Received April 24, 2016; Revision received June 13, 2016. Accepted June 23, 2016; First Published on June 23, 2016. We thank the present and former members of the Varshavsky laboratory, particularly K. Piatkov, for helpful discussions during this study. The authors declare no conflicts of interest with the contents of this article. Author contributions: B.W., A.V., J.B., Z.H., J.-H.O., and C-S.H. designed the experiments. B.W. performed the experiments, with participation by J.-H.O. B.W., A.V., and J.B. wrote the paper. All authors discussed the results and commented on the manuscript. This study was supported by the U.S. National Institutes of Health grants R01-DK039520 and R01-GM031530 (to A.V.), and by the R01-NS057583 grant (to J.B.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding AgencyGrant Number
Subject Keywords:acetyltransferase circadian proteolysis serotonin ubiquitin
Issue or Number:33
PubMed Central ID:PMC5016120
Record Number:CaltechAUTHORS:20160706-082440341
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Official Citation:Brandon Wadas, Jimo Borjigin, Zheping Huang, Jang-Hyun Oh, Cheol-Sang Hwang, and Alexander Varshavsky Degradation of Serotonin N-Acetyltransferase, a Circadian Regulator, by the N-end Rule Pathway J. Biol. Chem. 2016 291: 17178-. doi:10.1074/jbc.M116.734640
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:68845
Deposited By: Tony Diaz
Deposited On:06 Jul 2016 21:49
Last Modified:26 Apr 2022 17:55

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