Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy.
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Yang FC, Tan BC, Chen WH, Lin YH, Huang JY, Chang HY, Sun HY, Hsu PH, Liou GG, Shen J, Chang CJ, Han CC, Tsai MD, Lee SC
Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy.
J Biol Chem. 2013 Mar 1;288(9):6227-37. doi: 10.1074/jbc.M112.431239. Epub 2013 Jan 15.
- PubMed ID
- 23322770 [ View in PubMed]
- 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-deacetylation 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-43Delta 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.