Proteasome dysfunction in T cells causes immunodeficiency via cell cycle disruption and apoptosis

Proteasomes are essential molecular complex that regulate intracellular protein homeostasis by selectively degrading ubiquitinated proteins. Genetic mutations in subunits of proteasomes leads to proteasome-associated autoinflammatory syndromes (PRAAS) characterized by autoinflammation, partial progressive lipodystrophy, and in certain mutations, immunodeficiency. However, the molecular mechanisms by which proteasome dysfunction results in these phenotypes remain unclear. Here, we established a mouse that carries a mutation in β5i (encoded by Psmb8) along with T cell specific β5 (encoded by Psmb5) deficiency (KIKO mice). The KIKO mice showed severe loss of mature T cells in the spleen but not in the thymus, with reduced proteasome activity leading to the accumulation of ubiquitinated proteins. The CD4+ T cells of KIKO mice showed impaired proliferative activity with cell cycle arrest in G0/G1 phase following TCR engagement. T cells of KIKO mice underwent rapid cell death through apoptosis, as treatment of T cells with a caspase inhibitor Z-VAD rescued cell viability. Moreover, proteasome dysfunction induced apoptosis in T cells without either affecting mitochondrial functions or ER stress responses. Thus, our data provide insight into the molecular mechanisms underlying not only for immunodeficiency in PRAAS but also for T cell deficiency associated other disorders.