Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca2+ dynamics linked to DEE66

Truong Thi My Nhung; Nguyen Phuoc Long; Tran Diem Nghi; Yeongjun Suh; Nguyen Hoang Anh; Cheol Woon Jung; Hong Minh Triet; Minkyo Jung; Youngsik Woo; Jinyeong Yoo; Sujin Noh; Soo Jeong Kim; Su Been Lee; Seongoh Park; Gary Thomas; Thomas Simmen; Jiyoung Mun; Hyun-Woo Rhee; Sung Won Kwon; Sang Ki Park

doi:10.1073/pnas.2303402120

Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca²⁺ dynamics linked to DEE66

Proc Natl Acad Sci U S A. 2023 Aug 8;120(32):e2303402120. doi: 10.1073/pnas.2303402120. Epub 2023 Jul 31.

Authors

Truong Thi My Nhung¹, Nguyen Phuoc Long², Tran Diem Nghi¹, Yeongjun Suh¹, Nguyen Hoang Anh³, Cheol Woon Jung³, Hong Minh Triet¹, Minkyo Jung⁴, Youngsik Woo¹, Jinyeong Yoo¹, Sujin Noh¹, Soo Jeong Kim¹, Su Been Lee¹, Seongoh Park⁵, Gary Thomas⁶, Thomas Simmen⁷, Jiyoung Mun⁴, Hyun-Woo Rhee⁸, Sung Won Kwon³, Sang Ki Park¹

Affiliations

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

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.

Keywords: calcium; casein kinase 2; developmental and epileptic encephalopathy-66; mitochondria-associated ER membranes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Endoplasmic Reticulum* / metabolism
Mitochondria* / metabolism
Neurotransmitter Agents / metabolism
Phosphorylation

Substances

Neurotransmitter Agents

Grants and funding

R01 NS123649/NS/NINDS NIH HHS/United States