Genetic immunodeficiency and autoimmune disease reveals a WRC-independent role for Hem1 in mTORC2 regulation

Abstract

Abstract Inborn errors of immunity (IEI) are genetic disorders that cause life-threatening infections, lymphoproliferation, autoimmunity, or combinations of these features. We describe five patients from four families with a novel IEI characterized by recurrent infections, atopic disease, lymphoproliferation, cytokine overproduction, and autoimmunity. All patients harbored loss-of-function (LOF) variants in the gene NCKAP1L, which encodes the hematopoietic-specific Hem1 protein. Hem1 is a required component of the WAVE regulatory complex (WRC), a critical mediator of Arp2/3-dependent actin polymerization. Three LOF mutations impair interactions between Hem1 and other WRC components, resulting in degradation of the complex. A fourth mutation in Hem1 (M371V) abrogates activation of the WRC by Arf1 GTPase, resulting in WRC deficiency. Loss of Hem1 function disrupts Arp2/3-dependent actin polymerization, immune synapse formation, lamellipodia formation, and migration. Diminished cortical actin barriers in Hem1-deficient cells enable increased degranulation, cytokine secretion, and immune hyperresponsiveness leading to lymphoproliferation. Surprisingly, Hem1 deficiency causes reduced mTORC2-mediated AKT phosphorylation independently of its role in the actin polymerization. Dysregulation of the mTORC2/AKT axis leads to impaired T cell proliferation and effector cytokine production upon T cell activation. Our data show that Hem1 governs two key regulatory complexes, the WRC and mTORC2, and provide a cellular explanation for the combined immunodeficiency and immune hyperresponsiveness observed in Hem1-deficient patients. This research was supported by the Intramural Research Program of the NIH, NIAID.