JAK1-mediated Sirt1 phosphorylation functions as a negative feedback of the JAK1-STAT3 pathway.

Abstract

The type III NAD-dependent histone deacetylase Sirt1 plays important roles in a variety of pathobiological functions through targeting either the acetylated histones or transcription factors. However, the molecular mechanisms underlying how the Sirt1 functions are regulated remain vague. Herein we identified that the Janus kinase 1 (JAK1) interacts with Sirt1 and catalyzes its phosphorylation at the tyrosine residues of 280 and 301, both of which are highly conserved and located in the histone deacetylase catalytic domain of Sirt1. IL-6 stimulation enhanced Sirt1 interaction with JAK1 and JAK1-mediated Sirt1 phosphorylation. Interestingly, JAK1-mediated Sirt1 phosphorylation did not alter Sirt1 deacetylase catalytic activity, but instead it is required for Sirt1 interaction with the downstream transcription factor STAT3. JAK1-mediated phosphorylation enhanced Sirt1 suppression of STAT3 acetylation and transcriptional activity. As a consequence, Sirt1 activation attenuates IL-6 activity in protecting cancer cells from chemotherapeutic drug-induced apoptosis. Our studies identify JAK1 as a previously unappreciated tyrosine kinase of Sirt1 and reveal a novel negative feedback of the JAK1-STAT3 pathway.

• Authors: Wenhui Wang, Fei Li, Yuanming Xu, Juncheng Wei, Yana Zhang, Heeyoung Yang, Beixue Gao, Guohua Yu, Deyu Fang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 28 Pg. 11067-11075 (07 13 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29789426 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human
• Tyrosine
• JAK1 protein, human
• Janus Kinase 1
• SIRT1 protein, human
• Sirtuin 1

Topics

• Enzyme Activation
• Feedback, Physiological
• HEK293 Cells
• Humans
• Janus Kinase 1 (genetics, metabolism)
• Phosphorylation
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction
• Sirtuin 1 (genetics, metabolism)
• Tyrosine