Inflammation Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Sci Immunol. 2022 Sep 16;7(75):eabi4611. doi: 10.1126/sciimmunol.abi4611.
Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo is not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate with biallelic rare variants. Using patient-derived primary cells and biochemical assays, these variants were shown to behave as hypomorphic or knockout alleles that failed to repress NLRP1. The removal of a single copy of , , , or , but not , was sufficient to rescue the lethality of mutant neonates in mice. Similarly, deficiency was partially rescued by the inactivation of , an obligate downstream adapter of the NLRP1 inflammasome, in zebrafish. These experiments suggest that the deleterious consequences of DPP9 deficiency were mostly driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling. Collectively, our results delineate a Mendelian disorder of DPP9 deficiency driven by increased NLRP1 activity as demonstrated in patient cells and in two animal models of the disease.
二肽基肽酶 9（DPP9）是 NLRP1 的直接抑制剂，但它如何在体内影响炎症小体的调节尚不清楚。在这里，我们报道了三个具有免疫相关缺陷、生长不良、全血细胞减少和皮肤色素沉着异常的家族，这些缺陷与双等位基因罕见变异相关。使用患者来源的原代细胞和生化测定，这些变体表现为功能降低或缺失突变体，无法抑制 NLRP1。在小鼠中，去除 、 、 、或 中的一个拷贝，但不是 ，足以挽救 突变体新生儿的致死性。类似地，在斑马鱼中，NLRP1 炎症小体的必需下游衔接蛋白 的失活部分挽救了 缺陷。这些实验表明，DPP9 缺乏的有害后果主要是由 NLRP1 炎症小体和 IL-1β 信号的异常激活驱动的。总的来说，我们的结果描绘了一种由 NLRP1 活性增加驱动的 DPP9 缺乏症的孟德尔疾病，这在患者细胞和两种疾病的动物模型中得到了证实。
