PMID- 29769309 OWN - NLM STAT- MEDLINE DCOM- 20190117 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 293 IP - 26 DP - 2018 Jun 29 TI - Etoposide-induced protein 2.4 functions as a regulator of the calcium ATPase and protects pancreatic beta-cell survival. PG - 10128-10140 LID - 10.1074/jbc.RA118.002399 [doi] AB - Calcium homeostasis is essential for maintaining the viability and function of pancreatic beta cells and plays a key role in preventing the development of diabetes. Decreased levels of ATPase sarcoplasmic/endoplasmic reticulum Ca(2+)-transporting 2 (ATP2a2), the main calcium pump in beta cells, are often found in individuals with diabetes and in diabetic animal models. However, the regulators of ATP2a2 and the molecular mechanisms responsible for controlling ATP2a2 activity remain unclear. Etoposide-induced protein 2.4 (Ei24) is also down-regulated in beta cells of diabetic individuals, whereas the effect of decreased Ei24 level on beta-cell function is not clarified. Here, using Cre-LoxP and CRISPR/Cas9-based genomic knockout (KO) approaches to generate pancreatic beta cell-specific Ei24 KO mice and pancreatic beta-cell lines, we found that Ei24 regulates ATP2a2 activity. Specifically, we observed that Ei24 binds to ATP2a2 through Ei24 residues 293-299, which we named here the ATP2a2-interacting region (AIR). Loss of Ei24 inactivated ATP2a2, disrupted calcium homeostasis, and deactivated the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-AMP-activated protein kinase (AMPK) pathway. Elevation of calcium concentration in the endoplasmic reticulum or agonist-induced AMPK activation rescued pancreatic beta-cell survival and improved glucose tolerance of Ei24 KO mice. Our findings indicate that targeting the Ei24-ATP2a2 interaction to increase ATP2a2 activity can protect pancreatic beta cells and improve glucose homeostasis in diabetic models, suggesting that Ei24 could potentially serve as a target to prevent or manage diabetes. CI - (c) 2018 Yuan et al. FAU - Yuan, Lin AU - Yuan L AD - From the Key Laboratory of RNA Biology and. FAU - Wang, Huiyu AU - Wang H AD - From the Key Laboratory of RNA Biology and. AD - the College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100101. FAU - Liu, Qi AU - Liu Q AD - From the Key Laboratory of RNA Biology and. AD - the College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100101. FAU - Wang, Zhe AU - Wang Z AD - From the Key Laboratory of RNA Biology and. AD - the College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100101. FAU - Zhang, Mingshu AU - Zhang M AD - From the Key Laboratory of RNA Biology and. FAU - Zhao, Yan AU - Zhao Y AD - the National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101. FAU - Liang, Kuo AU - Liang K AD - the Department of General Surgery, XuanWu Hospital, Capital Medical University, Beijing 100053, and. FAU - Chen, Liangyi AU - Chen L AD - the State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China. FAU - Xu, Tao AU - Xu T AD - the College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100101, xutao@ibp.ac.cn. AD - the National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101. FAU - Xu, Pingyong AU - Xu P AD - From the Key Laboratory of RNA Biology and pyxu@ibp.ac.cn. AD - the College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100101. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180516 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (EI24 protein, human) RN - 0 (EI24 protein, mouse) RN - 0 (Nuclear Proteins) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - EC 2.7.11.17 (Camkk2 protein, mouse) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases) RN - EC 7.2.2.10 (ATP2A2 protein, human) RN - EC 7.2.2.10 (Atp2a2 protein, mouse) RN - SY7Q814VUP (Calcium) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Animals MH - Apoptosis Regulatory Proteins/deficiency/genetics/*metabolism MH - Calcium/metabolism MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism MH - Cell Line MH - Cell Survival MH - Diabetes Mellitus/genetics/metabolism/pathology MH - Energy Metabolism MH - Gene Knockout Techniques MH - Homeostasis MH - Humans MH - Insulin-Secreting Cells/*cytology/pathology MH - Mice MH - Nuclear Proteins/deficiency/genetics/*metabolism MH - Phenotype MH - Rats MH - Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism MH - Signal Transduction PMC - PMC6028951 OTO - NOTNLM OT - ATPase sarcoplasmic/endoplasmic reticulum Ca2+-transporting 2 OT - apoptosis OT - calcium ATPase OT - cell metabolism OT - diabetes OT - etoposide-induced protein 2.4 OT - glucose tolerance OT - pancreatic islet COIS- The authors declare that they have no conflicts of interest with the contents of this article EDAT- 2018/05/18 06:00 MHDA- 2019/01/18 06:00 PMCR- 2019/06/29 CRDT- 2018/05/18 06:00 PHST- 2018/02/12 00:00 [received] PHST- 2018/05/07 00:00 [revised] PHST- 2018/05/18 06:00 [pubmed] PHST- 2019/01/18 06:00 [medline] PHST- 2018/05/18 06:00 [entrez] PHST- 2019/06/29 00:00 [pmc-release] AID - S0021-9258(20)33852-7 [pii] AID - RA118.002399 [pii] AID - 10.1074/jbc.RA118.002399 [doi] PST - ppublish SO - J Biol Chem. 2018 Jun 29;293(26):10128-10140. doi: 10.1074/jbc.RA118.002399. Epub 2018 May 16.