Novel proteasome assembly chaperone mutations in PSMG2 /PAC2 cause the autoinflammatory interferonopathy CANDLE/PRAAS4

The ubiquitin-proteasome system is the primary homeostatic degradation system for ubiquitinated proteins, and proteasome dysfunction is associated with several human diseases including CANDLE/PRAAS.5,E4,E5 PAC2 is a proteasome assembly chaperone that dimerizes with PAC1, encoded by PSMG1, to form the PAC1/PAC2 complex.E6 Studies in different model systems showed a pivotal role of the PAC1/PAC2 complex in incorporating the proteasome α-subunits into the full 20S proteasome (see Fig E3 in this article's Online Repository at www.jacionline.org).E7-E10 To assess whether the novel mutations confer a LOF, we compared the proteolytic activity (chymotrypsin-, trypsin-, and caspase-like activities) of the proteasome in the patient's fibroblast lysates to lysates from disease controls of genetically confirmed CANDLE patients (DCs) and healthy controls. [...]the amount of assembled proteasome complexes was decreased (α6 staining), even when compared with the 2 DCs. Because only small amounts of mutant PSMG2/PAC2 variants were incorporated into nascent proteasome complexes, the impaired proteasome assembly (Fig 2, D) is conferred by reduced binding of the mutant PAC1/PAC2 heterodimer to the α-subunit of the proteasome core (Fig 2, D), which results in reduced proteasome assembly and activity (Fig 2, E). PAC2 is 1 of 3 assembly chaperones including POMP (“human Ump1”)E8-E10 and the PAC3/PAC4 heterodimer.E7 The 3 reported hypomorphic disease-causing POMP mutations are dominant due to haploinsufficiency (Fig E4),3,4 whereas the hypomorphic, disease-causing PSMG2 mutations are recessive, conferring additive LOF. Because both parents are asymptomatic, the wild-type allele in the heterozygous state can rescue function. Most patients with AIHA have IgG warm antibodies that trigger erythocyte phagocytosis, and a smaller subset has IgM antibodies that are cold activated, fix complement, and cause cold-type AIHA.6,E15,E16 AIHA has been reported in 2 patients with CANDLE,7,8 and is frequently seen in a spectrum of patients with immune dysregulatory diseases (eg, systemic lupus erythematosus, lymphoproliferative diseases including B-cell malignancies, and primary immunodeficiencies and infections)E17 and can present as hemolytic anemia and thrombocytopenia (Evans syndrome), which suggests that common genetic variants influence the development of AIHA.E15 Finally, the diagnosis of CANDLE/PRAAS led to treatment with the JAK inhibitor ruxolitinib, which inhibits the transduction of