title: Reversible acetylation regulates salt-inducible kinase (SIK2) and its function in autophagy.
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-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.
authors: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors: Fu-Chia
authors: FC
authors: Yang
authors: Bertrand Chin-Ming
authors: BC
authors: Tan
authors: Wei-Hao
authors: WH
authors: Chen
authors: Ya-Huei
authors: YH
authors: Lin
authors: Jing-Yi
authors: JY
authors: Huang
authors: Hsin-Yun
authors: HY
authors: Chang
authors: Hui-Yu
authors: HY
authors: Sun
authors: Pang-Hung
authors: PH
authors: Hsu
authors: Gunn-Guang
authors: GG
authors: Liou
authors: James
authors: J
authors: Shen
authors: Ching-Jin
authors: CJ
authors: Chang
authors: Chau-Chung
authors: CC
authors: Han
authors: Ming-Daw
authors: MD
authors: Tsai
authors: Sheng-Chung
authors: SC
authors: Lee
mesh_terms: D000107:Acetylation; D019943:Amino Acid Substitution; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000201:enzymology / Q000235:genetics; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics; D020125:Mutation, Missense; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D008239:Lysine