Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy

Fu Chia Yang, Bertrand Chin Ming Tan, Wei Hao Chen, Ya Huei Lin, Jing Yi Huang, Hsin Yun Chang, Hui Yu Sun, Pang Hung Hsu, Gunn Guang Liou, James Shen, Ching Jin Chang, Chau Chung Han, Ming Daw Tsai, Sheng Chung Lee

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Salt-inducible kinase 2 (SIK2) is a serine/threonine protein kinase belonging to the AMP-activated protein kinase (AMPK) family. SIK2 has been shown to function in the insulin-signaling pathway during adipocyte differentiation and to modulate CREB-mediated gene expression in response to hormones and nutrients. However, molecular mechanisms underlying the regulation of SIK2 kinase activity remains largely elusive. Here we report a dynamic, post-translational regulation of its kinase activity that is coordinated by an acetylation-deaceytlation switch, p300/CBP-mediated Lys-53 acetylation inhibits SIK2 kinase activity, whereas HDAC6-mediated deacetylation restores the activity. Interestingly, overexpression of acetylation- mimetic mutant of SIK2 (SIK2-K53Q), but not the nonacetylatable K53R variant, resulted in accumulation of autophagosomes. Further consistent with a role in autophagy, knockdown of SIK2 abrogated autophagosome and lysosome fusion. Consequently, SIK2 and its kinase activity are indispensable for the removal of TDP-43Δ inclusion bodies. Our findings uncover SIK2 as a critical determinant in autophagy progression and further suggest a mechanism in which the interplay among kinase and deacetylase activities contributes to cellular protein pool homeostasis.

Original languageEnglish
Pages (from-to)6227-6237
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number9
DOIs
Publication statusPublished - Mar 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Yang, F. C., Tan, B. C. M., Chen, W. H., Lin, Y. H., Huang, J. Y., Chang, H. Y., Sun, H. Y., Hsu, P. H., Liou, G. G., Shen, J., Chang, C. J., Han, C. C., Tsai, M. D., & Lee, S. C. (2013). Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy. Journal of Biological Chemistry, 288(9), 6227-6237. https://doi.org/10.1074/jbc.M112.431239