Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (T H 1) cells synthesized uridine diphosphate N -acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than T H 17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.

中文翻译：

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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 细胞代谢脆弱性


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对临床理解有限。虽然很少有基因被注释为同时导致 IEMs 和 IEIs，但免疫代谢需求表明更大的功能重叠。在这里，CRISPR 筛选测试了 IEM 基因的免疫作用和 IEI 基因的代谢效应，发现了大量以前未被重视的交叉。IEM 分析表明，N-连接糖基化和己糖胺途径酶 Gfpt1 对 T 细胞扩增和功能至关重要。此外，辅助性 T 细胞 （T H 1） 细胞合成尿苷二磷酸 N-乙酰氨基葡萄糖的速度比 T H 17 细胞更迅速，并且受 Gfpt1 缺陷的损害更大。筛选 IEI 基因发现 Bcl11b 促进 CD4 T 细胞线粒体活性和 Mcl1 表达，这是防止代谢应激所必需的。因此，IEM 和 IEI 基因之间存在高度的功能重叠，免疫代谢机制可能是这些疾病以前被低估的交叉的基础。