Reversible Acetylation Regulates Salt-inducible Kinase (SIK2) and Its Function in Autophagy*

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. Background: Salt-inducible kinase (SIK) 2 is an AMP-activated protein kinase family kinase that mediates hormonal and nutrient signaling but has no known link to cellular stress response. Results: p300/CBP and HDAC6 reciprocally regulates Lys-53 acetylation of SIK2, consequently impacting its activity and function in autophagosome maturation. Conclusion: SIK2 kinase activity, via a acetylation-based regulatory switch, contributes to autophagy progression. Significance: SIK2 may be linked to neurodegenerative or protein aggregate disorders.