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Proteasome-Associated Syndromes: Updates on Genetics, Clinical Manifestations, Pathogenesis, and Treatment

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Abstract

The ubiquitin–proteasome system (UPS) has a critical role in post-translational protein modification that is essential for the maintenance of all cellular functions, including immune responses. The proteasome complex is ubiquitously expressed and is responsible for degradation of short-lived structurally abnormal, misfolded and not-needed proteins that are targeted for degradation via ubiquitin conjugation. Over the last 14 years, an increasing number of human diseases have been linked to pathogenic variants in proteasome subunits and UPS regulators. Defects of the proteasome complex or its chaperons – which have a regulatory role in the assembly of the proteasome – disrupt protein clearance and cellular homeostasis, leading to immune dysregulation, severe inflammation, and neurodevelopmental disorders in humans. Proteasome-associated diseases have complex inheritance, including monogenic, digenic and oligogenic disorders and can be dominantly or recessively inherited. In this review, we summarize the current known genetic causes of proteasomal disease, and discuss the molecular pathogenesis of these conditions based on the function and cellular expression of mutated proteins in the proteasome complex.

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Funding

The works of QZ were supported by grants 82225022, 32141004 and 32321002 from The National Natural Science Foundation of China. The works of XY were supported by Hundred-Talent Program of Zhejiang University. The works of PT were supported by grants 82201926 from The National Natural Science Foundation of China, BX2021259 and 2021M702852 from China Postdoctoral Science Foundation.

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  1. Jiahui Zhang and Panfeng Tao contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, and Liangzhu Laboratory, Zhejiang University, Hangzhou, China

    Jiahui Zhang, Panfeng Tao, Xiaomin Yu & Qing Zhou

  2. National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Jiahui Zhang

  3. Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Natalie T. Deuitch & Ivona Askentijevich

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  1. Jiahui Zhang
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JZ and PT wrote the original draft, drew the figures and organized the table. XY provided valuable comments and modified the manuscript. IA, NTD and QZ reviewed and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Panfeng Tao, Xiaomin Yu or Qing Zhou.

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Zhang, J., Tao, P., Deuitch, N.T. et al. Proteasome-Associated Syndromes: Updates on Genetics, Clinical Manifestations, Pathogenesis, and Treatment. J Clin Immunol 44, 88 (2024). https://doi.org/10.1007/s10875-024-01692-y

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  • DOI: https://doi.org/10.1007/s10875-024-01692-y

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