Metabolic control of BRISC–SHMT2 assembly regulates immune signaling (Nature. 2019, 570(7760):194-199.)

報告日期: 2019/11/26
報告時間: 16:00/16:50
報告學生: 陳韋翔
講評老師: 王淑鶯
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Metabolic control of BRISC-SHMT2 assembly regulates immune signaling

Miriam Walden, et al. Nature 2019

Speaker: Wei-Hsiang Chen                 Time: 2019/11/26 16:10~17:00

Commenter: Prof. Shu-ying Wang       Place: Room 602

Abstract:

Serine hydroxymethyltransferase (SHMT) is a pyridoxal 5’-phosphate (PLP) dependent enzyme which involved in one carbon metabolism. Without PLP binding, SHMT2 forms dimeric structure in solution with unknown functions. PLP triggers structural change of SHMT2 from dimer to tetramer, an active state. Deubiquitylating BRCC36 isopeptidase complex (BRISC) is a deubiquitylaseresponsible for interferon 1 alpha receptor deubiquitination and improves immune signaling. Previous studies found that SHMT2 promotes type I interferon signaling through interacting with BRISC. However, the significance of the interaction between SHMT2-BRISC is still unclear. In this study, the authors used cryo-electron microscopy to present human SHMT2-BRISC complex structure at a resolution of 3.8 Å. They found that dimeric SHMT2 (without PLP-bound) inhibits deubiquitylase activity of BRISC by blocking BRCC36 active site. Mutations on SHMT2 and BRISC reduce SHMT2-BRISC interaction and attenuate interferon signaling. The binding of PLP promotes tetramerization of SHMT2, interfering SHMT2-BRISC complex formation and inflammatory cytokine responses. These results suggest that intracellular PLP levels may modulate immune signaling through SHMT2-BRISC interaction. This study provides evidences and mechanism linking vitamin metabolism with inflammation. These findings also imply the therapeutic potential of small-molecule ligands, such as folate and PLP analogues, on inflammatory diseases.

References:

  1. Zheng H, et al. A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep. 2013
  2. Giardina G, et al. How pyridoxal 5'-phosphate differentially regulates human cytosolic and mitochondrial serine hydroxymethyltransferase oligomeric state. FEBS J. 2015