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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.

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.

SUBMITTER: Kastnes M

PROVIDER: S-EPMC10258340 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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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.

Kastnes Martin M Aass Kristin Roseth KR Bouma Siri Anshushaug SA Årseth Charlotte C Zahoor Muhammad M Yurchenko Mariia M Standal Therese T

Frontiers in oncology 20230529

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 protei ...[more]

PMID: 37313466

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Project description:The post-translational attachment of one or several ubiquitin molecules to a protein generates a variety of targeting signals that are used in many different ways in the cell. Ubiquitination can alter the activity, localization, protein-protein interactions or stability of the targeted protein. Further, a very large number of proteins are subject to regulation by ubiquitin-dependent processes, meaning that virtually all cellular functions are impacted by these pathways. Nearly a hundred enzymes from five different gene families (the deubiquitinating enzymes or DUBs), reverse this modification by hydrolyzing the (iso)peptide bond tethering ubiquitin to itself or the target protein. Four of these families are thiol proteases and one is a metalloprotease. DUBs of the Ubiquitin C-terminal Hydrolase (UCH) family act on small molecule adducts of ubiquitin, process the ubiquitin proprotein, and trim ubiquitin from the distal end of a polyubiquitin chain. Ubiquitin Specific Proteases (USPs) tend to recognize and encounter their substrates by interaction of the variable regions of their sequence with the substrate protein directly, or with scaffolds or substrate adapters in multiprotein complexes. Ovarian Tumor (OTU) domain DUBs show remarkable specificity for different Ub chain linkages and may have evolved to recognize substrates on the basis of those linkages. The Josephin family of DUBs may specialize in distinguishing between polyubiquitin chains of different lengths. Finally, the JAB1/MPN+/MOV34 (JAMM) domain metalloproteases cleave the isopeptide bond near the attachment point of polyubiquitin and substrate, as well as being highly specific for the K63 poly-Ub linkage. These DUBs regulate proteolysis by: directly interacting with and co-regulating E3 ligases; altering the level of substrate ubiquitination; hydrolyzing or remodeling ubiquitinated and poly-ubiquitinated substrates; acting in specific locations in the cell and altering the localization of the target protein; and acting on proteasome bound substrates to facilitate or inhibit proteolysis. Thus, the scope and regulation of the ubiquitin pathway is very similar to that of phosphorylation, with the DUBs serving the same functions as the phosphatase. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.

Dataset Information

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.

Publications

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.

Similar Datasets

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