| Summary: | 博士 === 國立臺灣大學 === 生化科學研究所 === 101 === 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 mechanism underlying the regulation of SIK2 kinase activity remains largely elusive. In this study, I report a dynamic, post-translational regulation of its kinase activity that is coordinated by an acetylation-deaceytlation switch – p300/CBP-mediated Lys53-acetylation inhibits SIK2 kinase activity, while HDAC6-mediated deacetylation restores the activity. Interestingly, overexpression of acetylation-mimetic mutant of SIK2 (SIK2-K53Q), but not the non-acetylatable K53R variant, resulted in sequestration of SIK2 in 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. Remarkably, the accumulation of endogenous SIK2 in autophagosomes and the corresponding elevation of its acetylation were also observed in cells treated with MG132, yet not in serum-starved cells, revealing that this acetylation-based regulation may be induced by proteasome dysfunction and required for disposal of the resultant protein aggregates. Moreover, the requirement of SIK2 activity for retrotranslocation of ERAD substrate from ER to cytosol was evident. On the other hand, another SIK subfamily member, SIK3, was also modified reciprocally by CBP and HDAC6. In addition to SIK subfamily, the activity of MARK1 was under the control of CBP and HDAC6-mediated acetylation, implying its possible regulation in neurodegeneration diseases. Collectively, our findings uncover the critical roles of SIK2 in ERAD as well as autophagy progression and further suggest a mechanism in which the interplay among kinase and deacetylase activities coordinates cellular protein homeostasis.
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