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

• Published in: Frontiers in oncology 2023, Vol.13, p.1197542-1197542
• Main Authors: Kastnes, Martin, Aass, Kristin Roseth, Bouma, Siri Anshushaug, Årseth, Charlotte, Zahoor, Muhammad, Yurchenko, Mariia, Standal, Therese
• Format: Article
• Language: English
• Subjects: deubiquitinase (DUB); IL-32; multiple myeloma; Oncology; proteasome; T cells; ubiquitin (UB)
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2023.1197542

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.