Heterozygous missense variant of the proteasome subunit \u03b2-type 9 causes neonatal-onset autoinflammation and immunodeficiency

Nobuo Kanazawa,Naoko Wakaki-Nishiyama,Yuri Fukuda‐Ohta ,Akira Kinoshita,Hiroyuki Mishima,Shinobu Tamura,Kazuya Hamada,Yoshitaka Honda,Shigeo Murata,Ryuta Nishikomori,Miyuki Tsumura,Norio Kawamoto,Hiroyuki Ohnishi ,Noriko Kinjo,Satoshi Okada,Kayo Kunimoto,Takashi Orimo,Jun Hamazaki,Satoru Hamada,Yutaka Inaba,Izumi Sasaki,Hiroaki Hemmi,Yusuke Yamashita,Koichi Nakanishi,Takashi Kato,Toshiya Ozasa,Kazushi Izawa,Tsunehiro Mizushima,Takeshi Taketani,Koh-Ichiro Yoshiura,Saori Kadowaki,Tsuneyasu Kaisho

doi:10.1038/s41467-021-27085-y

Abstract

Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9G156D/+) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.

Highlights

Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS)
We describe a de novo heterozygous missense variant, p.G156D, in PSMB9 coding an immunoproteasome subunit, β1i, in two unrelated patients that manifest characteristic autoinflammation, similar to, but distinct from so far described PRAAS, with immunodeficiency
The variant led to defects in β1i maturation and formation and activity of immunoproteasome, it mainly caused formation and activity defects in the 20S complex, and the 26S proteasome defects were mild enough at least to avoid ubiquitin accumulation, as shown by the analysis of the present two patients and of the mice carrying the heterozygous or homozygous PSMB9 G156D mutation (Supplementary Fig. 8)

Summary

Introduction

Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). We report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. Immunoproteasome and thymoproteasome are involved in protein degradation and in generation of antigen peptides presented with major histocompatibility complex (MHC) class I molecules and CD8 T cell repertoire, population, and responses. We identify a de novo PSMB9 heterozygous missense variant, G156D, in two unrelated Japanese patients with manifestations, including autoinflammation and immunodeficiency, which are similar to, but distinct from those of PRAAS patients. The proteasome defect and immunodeficient phenotypes are recapitulated in Psmb9G156D/+ mice

Methods

Results

Conclusion