NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation

Huibing Wang, Weiwei Qi, Chengyu Zou, Zhangdan Xie, Mengmeng Zhang, Masanori Gomi Naito, Lauren Mifflin, Zhen Liu, Ayaz Najafov, Heling Pan, Bing Shan, Ying Li, Zheng-Jiang Zhu and Junying Yuan ()
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Huibing Wang: Department of Cell Biology, Harvard Medical School
Weiwei Qi: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Chengyu Zou: Department of Cell Biology, Harvard Medical School
Zhangdan Xie: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Mengmeng Zhang: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Masanori Gomi Naito: Department of Cell Biology, Harvard Medical School
Lauren Mifflin: Department of Cell Biology, Harvard Medical School
Zhen Liu: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Ayaz Najafov: Department of Cell Biology, Harvard Medical School
Heling Pan: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Bing Shan: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Ying Li: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Zheng-Jiang Zhu: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Junying Yuan: Department of Cell Biology, Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Loss-of-function mutations in NEK1 gene, which encodes a serine/threonine kinase, are involved in human developmental disorders and ALS. Here we show that NEK1 regulates retromer-mediated endosomal trafficking by phosphorylating VPS26B. NEK1 deficiency disrupts endosomal trafficking of plasma membrane proteins and cerebral proteome homeostasis to promote mitochondrial and lysosomal dysfunction and aggregation of α-synuclein. The metabolic and proteomic defects of NEK1 deficiency disrupts the integrity of blood–brain barrier (BBB) by promoting lysosomal degradation of A20, a key modulator of RIPK1, thus sensitizing cerebrovascular endothelial cells to RIPK1-dependent apoptosis and necroptosis. Genetic inactivation of RIPK1 or metabolic rescue with ketogenic diet can prevent postnatal lethality and BBB damage in NEK1 deficient mice. Inhibition of RIPK1 reduces neuroinflammation and aggregation of α-synuclein in the brains of NEK1 deficient mice. Our study identifies a molecular mechanism by which retromer trafficking and metabolism regulates cerebrovascular integrity, cerebral proteome homeostasis and RIPK1-mediated neuroinflammation.

Date: 2021
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DOI: 10.1038/s41467-021-25157-7

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