title: Interaction between salt-inducible kinase 2 (SIK2) and p97/valosin-containing protein (VCP) regulates endoplasmic reticulum (ER)-associated protein degradation in mammalian cells.
abstract: Salt-inducible kinase 2 (SIK2) is an important regulator of cAMP response element-binding protein-mediated gene expression in various cell types and is the only AMP-activated protein kinase family member known to interact with the p97/valosin-containing protein (VCP) ATPase. Previously, we have demonstrated that SIK2 can regulate autophagy when proteasomal function is compromised. Here we report that physical and functional interactions between SIK2 and p97/VCP underlie the regulation of endoplasmic reticulum (ER)-associated protein degradation (ERAD). SIK2 co-localizes with p97/VCP in the ER membrane and stimulates its ATPase activity through direct phosphorylation. Although the expression of wild-type recombinant SIK2 accelerated the degradation and removal of ERAD substrates, the kinase-deficient variant conversely had no effect. Furthermore, down-regulation of endogenous SIK2 or mutation of the SIK2 target site on p97/VCP led to impaired degradation of ERAD substrates and disruption of ER homeostasis. Collectively, these findings highlight a mechanism by which the interplay between SIK2 and p97/VCP contributes to the regulation of ERAD in mammalian cells.
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Fu-Chia
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Wei-Hao
authors.initials: WH
authors.lastname: Chen
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Hsin-Yun
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Su-Hui
authors.initials: SH
authors.lastname: Su
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Hsiao-Ting
authors.initials: HT
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Chiang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Pang-Hung
authors.initials: PH
authors.lastname: Hsu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan; Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ming-Daw
authors.initials: MD
authors.lastname: Tsai
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Tao-Yuan 33302, Taiwan.
authors.forename: Bertrand Chin-Ming
authors.initials: BC
authors.lastname: Tan
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan; Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan; Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: slee@ntu.edu.tw.
authors.forename: Sheng-Chung
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: ER Stress; ER-associated Degradation; ERAD; Protein Degradation; SIK2; Unfolded Protein Response; p97/VCP