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

Martin Kastnes; Kristin Roseth Aass; Siri Anshushaug Bouma; Charlotte Årseth; Muhammad Zahoor; Mariia Yurchenko; Therese Standal

doi:10.3389/fonc.2023.1197542

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

Front Oncol. 2023 May 29:13:1197542. doi: 10.3389/fonc.2023.1197542. eCollection 2023.

Authors

Martin Kastnes¹, Kristin Roseth Aass¹, Siri Anshushaug Bouma¹, Charlotte Årseth¹, Muhammad Zahoor², Mariia Yurchenko¹, Therese Standal^{1

3}

Affiliations

¹ Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
² Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
³ Department of Hematology, St.Olavs University Hospital, Trondheim, Norway.

Abstract

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.

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

Grants and funding

This work was supported by funds from the Norwegian Cancer Society (No. 198161), The Research Council of Norway (No. 274991, No. 223255), The Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. (No. 90171600, No. 90635300, No. 30171600) and the Cancer Fund at St.Olavs Hospital.