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

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.

Rickettsial pathogen inhibits tick cell death through tryptophan metabolite mediated activation of p38 MAP kinase

“…Studies have reported that Phospholipase D3 (PLD3), Senescence marker protein 30 (SMP30), Syntaxin and Vacuolar protein sorting 26B (VPS26B) proteins are involved in cell death process. 36 , 37 , 38 , 39 I . scapularis ticks encodes all these genes in their genome ( Table S1 ).…”

SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation

“…We have recently reported the role of necroptosis in cerebromicrovascular endothelial cells mediated by RIPK1 and RIPK3 in promoting the BBB damage in Alzheimer’s disease 59 and in Nek1-deficient mice. 60 Future studies may be needed to directly investigate the role of necroptosis in mediating CNS invasion by SARS-CoV-2.…”

SNX27–Retromer directly binds ESCPE-1 to transfer cargo proteins during endosomal recycling

“…A well-characterized example of cargo tail phosphorylation modulating SNX27 affinity and subsequent endosomal sorting is the β2AR [ 29 , 63 ]. Furthermore, phosphorylation of SNX27 at Ser-51 alters the conformation of its PDZbm-binding pocket decreasing the affinity for cargo proteins, thereby inhibiting endosomal sorting [ 64 ] and Ser-302 and Ser-304 phosphorylation in VPS26B can modulate SNX27 association [ 65 ]. Similarly, ESCPE-1 function can be regulated by phosphorylation; in this case, Ser-226 of SNX5 undergoes phosphorylation, which decreases dimerization with SNX1 and SNX2 and reduces endosomal recycling [ 66 ].…”