The pro-tumorigenic cytokine IL-32 has a high turnover in multiple myeloma cells due to proteolysis regulated by oxygen-sensing cysteine dioxygenase and deubiquitinating enzymes

Frontiers in Oncology

Oncology

Charlotte Årseth¹  Siri Anshushaug Bouma¹  Kristin Roseth Aass¹  Martin Kastnes¹  Mariia Yurchenko¹  Therese Standal²  Muhammad Zahoor³ 

[1] Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway;Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway;Department of Hematology, St.Olavs University Hospital, Trondheim, Norway;Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway;

关键词: multiple myeloma;    proteasome;    ubiquitin (UB);    IL-32;    T cells;    deubiquitinase (DUB);    oxygen stress;    ADO;   

DOI  :  10.3389/fonc.2023.1197542

 received in 2023-03-31, accepted in 2023-05-16,  发布年份 2023

来源: Frontiers

【 摘 要 】

IL-32 is a pro-inflammatory cytokine expressed by several types of cancer cells and immune cells. Currently, no treatment targeting IL-32 is available, and its intracellular and exosomal localization make IL-32 less accessible to drugs. We previously showed that hypoxia promotes IL-32 expression through HIF1α in multiple myeloma cells. Here, we demonstrate that high-speed translation and ubiquitin-dependent proteasomal degradation lead to a rapid IL-32 protein turnover. We find that IL-32 protein half-life is regulated by the oxygen-sensing cysteine-dioxygenase ADO and that deubiquitinases actively remove ubiquitin from IL-32 and promote protein stability. Deubiquitinase inhibitors promoted the degradation of IL-32 and may represent a strategy for reducing IL-32 levels in multiple myeloma. The fast turnover and enzymatic deubiquitination of IL-32 are conserved in primary human T cells; thus, deubiquitinase inhibitors may also affect T-cell responses in various diseases.

【 授权许可】

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Copyright © 2023 Kastnes, Aass, Bouma, Årseth, Zahoor, Yurchenko and Standal