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

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 120; no. 32; p. e2303402120
Main Authors Nhung, Truong Thi My, Long, Nguyen Phuoc, Nghi, Tran Diem, Suh, Yeongjun, Anh, Nguyen Hoang, Jung, Cheol Woon, Triet, Hong Minh, Jung, Minkyo, Woo, Youngsik, Yoo, Jinyeong, Noh, Sujin, Kim, Soo Jeong, Lee, Su Been, Park, Seongoh, Thomas, Gary, Simmen, Thomas, Mun, Jiyoung, Rhee, Hyun-Woo, Kwon, Sung Won, Park, Sang Ki
Format Journal Article
LanguageEnglish
Published Washington National Academy of Sciences 08.08.2023
Subjects
Biological Sciences
Calcium (mitochondrial)
Calcium homeostasis
Calcium influx
Calcium ions
Calcium signalling
Calcium transport
Casein
Casein kinase II
Encephalopathy
Endoplasmic reticulum
Epilepsy
Genomes
Glutamatergic transmission
Homeostasis
Kinases
Localization
Mitochondria
Molecular modelling
Mutation
Neurotransmitter release
Neurotransmitters
Phosphorylation
Presynapse
Screening
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Summary: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.
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Edited by Luca Scorrano, Universita degli Studi di Padova, Padua, Italy; received February 28, 2023; accepted June 15, 2023 by Editorial Board Member Jeremy Nathans
1T.T.M.N. and N.P.L. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2303402120