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全基因组激酶-MAM 相互作用组筛选揭示 CK2A1 在与 DEE66 相关的 MAM Ca 动力学中的作用。

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

机构信息

Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.

Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea.

出版信息

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

DOI:10.1073/pnas.2303402120
PMID:37523531
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10410754/
Abstract

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca 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 Ca 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 Ca 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 Ca uptake and the dramatic increase of the cytosolic Ca 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 Ca-dependent neurotransmitter release.

摘要

内质网（ER）和线粒体形成了一个独特的细胞区室，称为线粒体相关内质网膜（MAMs）。MAMs 的破坏会破坏 Ca 稳态，在神经元系统中引发多种效应。全基因组激酶-MAM 相互作用组筛选鉴定出酪蛋白激酶 2α1（CK2A1）是 MAMs 组成和 Ca 转运的调节剂。CK2A1 介导的 PACS2 丝氨酸 207/208/213 磷酸化促进 CK2A1-PACS2-PKD2 复合物在 MAMs 上的定位，调节 PKD2 依赖性线粒体 Ca 内流。我们进一步揭示与发育性和癫痫性脑病-66（DEE66）相关的 PACS2（E209K 和 E211K）突变通过干扰 PACS2 丝氨酸 207/208/213 的磷酸化破坏 MAMs 的完整性。这反过来又导致线粒体 Ca 摄取减少和细胞溶质 Ca 水平的急剧增加，从而在谷氨酸能神经元的轴突末梢诱导神经递质释放。总之，我们的研究结果表明，病理 PACS2 突变引起的 MAMs 改变调节 Ca 依赖性神经递质释放的分子机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/c3ad45189ae1/pnas.2303402120fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/4015df7bf618/pnas.2303402120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/1a9238cc8010/pnas.2303402120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/bc5a3916aca5/pnas.2303402120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/3392b9e98daf/pnas.2303402120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/e4c08baca4a2/pnas.2303402120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/8fb4eed098e1/pnas.2303402120fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/c3ad45189ae1/pnas.2303402120fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/4015df7bf618/pnas.2303402120fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/1a9238cc8010/pnas.2303402120fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/bc5a3916aca5/pnas.2303402120fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/3392b9e98daf/pnas.2303402120fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/e4c08baca4a2/pnas.2303402120fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/8fb4eed098e1/pnas.2303402120fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/536a/10410754/c3ad45189ae1/pnas.2303402120fig07.jpg

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