HERC5-HSP60 ISGylation Axis Sustains Mitochondrial Homeostasis in Glioblastoma Stem Cells to Promote Tumor Progression

Within the tumor microenvironment, dynamic crosstalk between GSCs and cytokines creates a niche for GSC maintenance. While interferon-gamma (IFN-γ) plays a well-established role in antitumor immunity, we reveal its paradoxical function in promoting the proliferation and self-renewal of GSCs.

In this study, we show that IFN-γ induces the expression of HECT and RLD domain-containing E3 ubiquitin ligase 5 (HERC5) in GSCs, which functions as an ISG15 E3 ligase. HERC5 promotes mitochondrial stability by mediating the ISGylation of heat shock protein 60 (HSP60), a key mitochondrial chaperone. Genetic depletion of HERC5 leads to HSP60 degradation, mitochondrial dysfunction, and marked suppression of tumor growth, significantly prolonging survival in orthotopic GBM mouse models.