Kastnes Martin, Aass Kristin Roseth, Bouma Siri Anshushaug, Årseth Charlotte, Zahoor Muhammad, Yurchenko Mariia, Standal Therese
Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Front Oncol. 2023 May 29;13:1197542. doi: 10.3389/fonc.2023.1197542. eCollection 2023.
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.
白细胞介素-32（IL-32）是一种由多种癌细胞和免疫细胞表达的促炎细胞因子。目前，尚无针对IL-32的治疗方法，其在细胞内和外泌体中的定位使得药物难以作用于IL-32。我们之前表明，缺氧通过缺氧诱导因子1α（HIF1α）促进多发性骨髓瘤细胞中IL-32的表达。在此，我们证明高速翻译和泛素依赖性蛋白酶体降解导致IL-32蛋白快速周转。我们发现IL-32蛋白半衰期受氧感应半胱氨酸双加氧酶ADO调节，去泛素酶可积极去除IL-32上的泛素并促进蛋白稳定性。去泛素酶抑制剂促进了IL-32的降解，可能代表了一种降低多发性骨髓瘤中IL-32水平的策略。IL-32的快速周转和酶促去泛素化在原代人T细胞中是保守的；因此，去泛素酶抑制剂也可能影响各种疾病中的T细胞反应。
