Interaction between Salt-inducible Kinase 2 (SIK2) and p97/Valosin-containing Protein (VCP) Regulates Endoplasmic Reticulum (ER)-associated Protein Degradation in Mammalian Cells
|
| |
Authors: | Fu-Chia Yang Ya-Huei Lin Wei-Hao Chen Jing-Yi Huang Hsin-Yun Chang Su-Hui Su Hsiao-Ting Wang Chun-Yi Chiang Pang-Hung Hsu Ming-Daw Tsai Bertrand Chin-Ming Tan Sheng-Chung Lee |
| |
Institution: | From the Institutes of ‡Molecular Medicine and ;**Clinical Medicine, National Taiwan University, Taipei 100, Taiwan.;§Genomics Research Center and ;¶Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan, and ;‖Department of Biomedical Sciences, Chang Gung University, Tao-Yuan 33302, Taiwan |
| |
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. |
| |
Keywords: | ER Stress ER-associated Degradation ERAD Protein Degradation Unfolded Protein Response SIK2 p97/VCP |
|
|