Identification of potential substrates of TRABID in HeLa cells using SILAC

ABSTRACT: Immune checkpoint blockades (ICBs) have been approved for treating multiple cancer types, but the response rate is limited for many solid tumors. Much efforts have been devoted to understand the mechanisms governing ICB therapy efficacy and the abundance of tumor-infiltrating lymphocytes is among the factors that influence on ICB responsiveness. The deubiquitinase TRABID was identified in our previous study as a positive regulator of autophagy by stabilizing VPS34, the class III PI3K critical for autophagosome formation. In this study, we identify an upregulation of TRABID in mitosis and its critical role in mitotic progression through deubiquitination and stabilization of AURKB and BIRC5, two subunits of the chromosome passenger complex governing multiple mitotic steps. Furthermore, TRABID depletion induces micronuclei phenotype, which is likely mediated by the combinatory defects in mitosis and autophagy. Consequently, TRABID depletion or inhibition activates cGAS/STING pathway to induce type I interferon production and inflammatory responses. TRABID depletion in tumors cells reduces tumor burden and promotes anti-tumor immune surveillance by increasing tumor infiltration of CD4+ and CD8+ T cells and NK cells and reducing Treg cells. Clinically, TRABID expression in multiple cancer types correlates negatively with the infiltration of anti-tumor immune cells and positively with that of pro-tumor immune cells. Our study supports a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and suggests TRABID inhibitor as a promising agent for enhancing the sensitivity of solid tumors to ICB therapy.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: CHEN HAN-HSIUN  

LAB HEAD: Ruey-Hwa Chen

PROVIDER: PXD035002 | Pride | 2023-05-11

REPOSITORIES: Pride