利兹大学Elton Zeqiraj研究小组近日取得一项新成果，他们揭示了BRISC–SHMT2组装的代谢控制调节免疫信号。相关论文于2019年5月29日发表在《自然》杂志上。

课题组人员展示了人类BRISC-SHMT2复合物的低温电子显微镜结构，分辨率为3.8Å。BRISC是有四个亚基的U型二聚体，SHMT2空间上阻断BRCC36活性位点，抑制去泛素酶活性。只有不活跃的SHMT2二聚体-而不是活化PLP结合的四聚体-可以结合和抑制BRISC。突变破坏SHMT2结合BRISC抑制I型干扰素信号通路对炎症刺激的反应。细胞内PLP水平调节BRISC和SHMT2之间的相互作用，以及炎症细胞因子的反应。这些数据揭示了代谢物调节去泛素酶活性和炎症信号的机制。

研究人员表示，丝氨酸羟甲基转移酶2 (SHMT2)调节单碳转移反应，这是氨基酸和核苷酸代谢必不可少的，利用吡啶醛5‘磷酸(PLP)作为一个辅助因子。Apo SHMT2是一种功能未知的二聚体，而PLP的结合稳定了活性四聚体状态。SHMT2还通过与去泛素化的BRCC36异肽酶复合物(BRISC)相互作用促进炎症细胞因子信号传递，尽管尚不清楚该功能是否与代谢有关。

附：英文原文

Title: Metabolic control of BRISC–SHMT2 assembly regulates immune signalling

Author:Miriam Walden, Lei Tian, Rebecca L. Ross, Upasana M. Sykora, Dominic P. Byrne, Emma L. Hesketh, Safi K. Masandi, Joel Cassel, Rachel George, James R. Ault, Farid El Oualid, Krzysztof Paw?owski, Joseph M. Salvino, Patrick A. Eyers, Neil A. Ranson, Francesco Del Galdo, Roger A. Greenberg & Elton Zeqiraj

Issue&Volume: Volume 570 Issue 7760, 13 June 2019

Abstract: Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5′-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC–SHMT2 complex at a resolution of 3.8 . BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer—and not the active PLP-bound tetramer—binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.

DOI: https://doi.org/10.1038/s41586-019-1232-1

Source: https://www.nature.com/articles/s41586-019-1232-1