Truong Thi My Nhung (POSTECH)

한빛사논문

조회636

POSTECH

Proc. Natl. Acad. Sci. USA, 2023 Aug 8;120(32):e2303402120 | https://doi.org/10.1073/pnas.2303402120 Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca2+ dynamics linked to DEE66

Truong Thi My Nhung ^1 †, Nguyen Phuoc Long ^2 †, Tran Diem Nghi ¹, Yeongjun Suh ¹, Nguyen Hoang Anh ³, Cheol Woon Jung ³, Hong Minh Triet ¹, Minkyo Jung ⁴, Youngsik Woo ¹, Jinyeong Yoo ¹, Sujin Noh ¹, Soo Jeong Kim ¹, Su Been Lee ¹, Seongoh Park ⁵, Gary Thomas ⁶, Thomas Simmen ⁷, Jiyoung Mun ⁴, Hyun-Woo Rhee ⁸, Sung Won Kwon ³, Sang Ki Park ^{1 *}

¹Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
²Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea.
³College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
⁴Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea.
⁵School of Mathematics, Statistics and Data Science, Sungshin Women's University, Seoul 02844, Republic of Korea.
⁶Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA 15219.
⁷Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
⁸Department of Chemistry, Seoul National University, Seoul 08826, Korea.

^†T.T.M.N. and N.P.L. contributed equally to this work
^*Corresponding author: correspondence to Sang Ki Park

Abstract

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca²⁺ homeostasis, triggering pleiotropic effects in the neuronal system. Genome-wide kinase-MAM interactome screening identifies casein kinase 2 alpha 1 (CK2A1) as a regulator of composition and Ca²⁺ transport of MAMs. CK2A1-mediated phosphorylation of PACS2 at Ser207/208/213 facilitates MAM localization of the CK2A1–PACS2–PKD2 complex, regulating PKD2-dependent mitochondrial Ca²⁺ influx. We further reveal that mutations of PACS2 (E209K and E211K) associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity through the disturbance of PACS2 phosphorylation at Ser207/208/213. This, in turn, causes the reduction of mitochondrial Ca²⁺ uptake and the dramatic increase of the cytosolic Ca²⁺ level, thereby, inducing neurotransmitter release at the axon boutons of glutamatergic neurons. In conclusion, our findings suggest a molecular mechanism that MAM alterations induced by pathological PACS2 mutations modulate Ca²⁺-dependent neurotransmitter release.

논문정보

형식Research article
게재일2023년 08월 (BRIC 등록일 2023-08-01)
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학

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