TY - JOUR
T1 - NEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation
AU - Wang, Huibing
AU - Qi, Weiwei
AU - Zou, Chengyu
AU - Xie, Zhangdan
AU - Zhang, Mengmeng
AU - Naito, Masanori Gomi
AU - Mifflin, Lauren
AU - Liu, Zhen
AU - Najafov, Ayaz
AU - Pan, Heling
AU - Shan, Bing
AU - Li, Ying
AU - Zhu, Zheng Jiang
AU - Yuan, Junying
N1 - Funding Information:
The authors thank Dr. Vishva Dixit of Genentech for K63 ubiquitin chain ab, Drs. Michelle Kelliher (University of Massachusetts) and Manolis Pasparakis (University of Cologne, Germany) for providing Ripk1D138N mice. We thank the Nikon Imaging Center at Harvard Medical School for assistance with microscopy. This work was supported in part by the HMS loyalty income (to JY), the China National Natural Science Foundation (21837004 and 91849204),the Chinese Academy of Sciences (XDB39030200) the National Key R&D Program of China (2016YFA0501900) and China National Natural Science Youth Foundation (31701210, 31801163).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-25157-7
DO - 10.1038/s41467-021-25157-7
M3 - Article
C2 - 34376696
AN - SCOPUS:85112028790
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4826
ER -