臺大醫學院-分子醫學研究所;臺大醫學院-臨床醫學研究所;Yang, Fu-ChiaFu-ChiaYangTan, Bertrand Chin-MingBertrand Chin-MingTanChen, Wei-HaoWei-HaoChenLin, Ya-HueiYa-HueiLinHuang, Jing-YiJing-YiHuangChang, Hsin-YunHsin-YunChangSun, Hui-YuHui-YuSunHsu, Pang-HungPang-HungHsuLiou, Gunn-GuangGunn-GuangLiouShen, JamesJamesShenChang, Ching-JinChing-JinChangHan, Chau-ChungChau-ChungHanTsai, Ming-DawMing-DawTsaiLee, Sheng-ChungSheng-ChungLee2017-06-222018-07-092017-06-222018-07-092013http://ntur.lib.ntu.edu.tw//handle/246246/279524Salt-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-43 Delta 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.10.1074/jbc.M112.431239