Liu Rui,Zeng Lin-Wen,Li Hui-Fang,Shi Jun-Ge,Zhong Bo,Shu Hong-Bing,Li Shu
Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γ c ). PD-1 ligation also activates SHP2, which dephosphorylates γ c Y357 , leading to impairment of γ c family cytokine-triggered signaling. Conversely, PD-1 blockade restores γ c level and activity, thereby sensitizing CD8 + T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γ c family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.
Post-traumatic septic myocardial dysfunction (PT-SIMD) is a life-threatening condition with high mortality and no specific treatment. Ferroptosis, an iron-dependent regulated cell death pathway driven by lipid peroxidation, has been implicated in septic cardiac injury, yet the endogenous mechanisms that counteract this process remain poorly understood. We aimed to identify novel cardioprotective regulators of ferroptosis in PT-SIMD using unbiased proteomics and to investigate whether the GLP-1 receptor agonist semaglutide (SEMA) confers protection through modulation of mitochondrial E3 ubiquitin ligases. In a rat model combining limb crush injury and cecal ligation and puncture (CLP), PT-SIMD was accompanied by marked myocardial ferroptosis, evidenced by elevated ACSL4, reduced GPX4/FSP1, and 4-HNE accumulation. Quantitative 4D-DIA proteomic profiling identified March5, a mitochondrial E3 ubiquitin ligase, as significantly downregulated. In primary neonatal rat ventricular myocytes, LPS exposure suppressed March5 expression in a dose- and time-dependent manner. Knockdown of March5 using siRNA exacerbated LPS-induced ferroptosis, increasing ACSL4 protein levels, labile Fe2+, and lipid peroxidation. Notably, SEMA treatment upregulated March5 expression, attenuated ACSL4 accumulation, and ameliorated ferroptotic injury. Crucially, siRNA-mediated silencing of March5 in cardiomyocytes completely abolished the anti-ferroptotic and cytoprotective effects of SEMA. Collectively, March5 functions as a critical endogenous suppressor of ferroptosis in PT-SIMD by negatively regulating ACSL4. Semaglutide exerts its cardioprotective action via March5-dependent inhibition of the ACSL4 ferroptosis axis, highlighting a promising therapeutic strategy for sepsis-associated myocardial dysfunction.
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