Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities.
Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities.
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免疫和代谢基因先天性缺陷的功能重叠定义了 T 细胞免疫代谢脆弱性。
DOI：
10.1101/2023.01.24.525419
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Rathmell,JeffreyC
中科院分区：
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作者：
Patterson,AndrewR;Needle,GabrielA;Sugiura,Ayaka;Chi,Channing;Steiner,KayLeeK;Fisher,EmilieL;Robertson,GabriellaL;Bodnya,Caroline;Markle,JanetG;Gama,Vivian;Rathmell,JeffreyC
先天性代谢缺陷（IEM）和免疫缺陷（IEI）是孟德尔疾病，其中复杂的表型和患者罕见性可能限制临床注释。很少有基因被分配给IEM和IEI，但免疫代谢的需求表明功能重叠被低估了。我们应用CRISPR筛选来测试IEM基因的免疫作用和IEI基因的代谢作用，并发现了相当大的交叉。IEM分析表明，N-连接的糖基化和脱novohexosamine合成酶Gfpt 1对T细胞的扩增和功能至关重要。有趣的是，Gfpt 1缺陷型TH 1细胞比TH 17细胞受到的影响更大，TH 17细胞增加了挽救UDP-GlcNAc合成的Nagk。筛选IEI基因显示转录因子Bcl 11b促进CD 4 +T细胞线粒体活性和Mcl 1表达，这是防止代谢应激所必需的。这些数据说明IEM和IEI基因的高度功能重叠，并指出了以前未被认识到的一组这些疾病的潜在免疫代谢机制。重点免疫和代谢的先天性缺陷比以前已知的重叠更大Gfpt 1缺陷导致IEM，但也选择性地调节T细胞亚群命运Bcl 11b的缺失导致T细胞缺陷IEI，但也损害线粒体功能许多IEM可能具有免疫缺陷IEI可能是由代谢机制驱动的
Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and thede novohexosamine synthesis enzyme,Gfpt1, are critical for T cell expansion and function. Interestingly,Gfpt1-deficient TH1 cells were more affected than TH17 cells, which had increasedNagkfor salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factorBcl11bpromotes CD4+T cell mitochondrial activity andMcl1expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders.HIGHLIGHTSInborn errors of immunity and metabolism have greater overlap than previously knownGfpt1deficiency causes an IEM but also selectively regulates T cell subset fateLoss ofBcl11bcauses a T cell deficiency IEI but also harms mitochondrial functionMany IEM may have immune defects and IEI may be driven by metabolic mechanisms