NRGN inhibits CD8⁺ T cell effector function by downregulating MHC-I expression through the FMR1-IRF8 axis in hepatocellular carcinoma.
Abstract
Background
Neurogranin (NRGN) has been extensively studied as a neuron-enriched synaptic regulatory protein, yet its function in cancer remains largely unexplored. Immune evasion driven by defective antigen presentation and CD8⁺ T cell dysfunction is a hallmark of hepatocellular carcinoma (HCC). This study aimed to determine whether NRGN contributes to immune escape in HCC and to elucidate its underlying molecular mechanism.
Methods
NRGN expression and clinical relevance were analyzed in public datasets and validated in HCC tissues. Transcriptomic and enrichment analyses assessed antigen presentation. Gain- and loss-of-function experiments were performed in human and murine HCC cells, while orthotopic and subcutaneous models with CD8⁺ T cell exhaustion, β2M knockout, and H-2Kb blockade evaluated immune dependence in vivo. RNA stability, RNA pulldown, RIP, co-immunoprecipitation, ubiquitination, and luciferase assays were conducted to define the molecular mechanisms.
Results
NRGN was significantly upregulated in HCC and associated with advanced stage and poor survival, correlating inversely with GZMB⁺ CD8⁺ T cell infiltration. NRGN knockdown enriched MHC-I antigen presentation pathways and restored MHC-I/β2M expression, tumor cell surface antigen presentation, and CD8⁺ T cell cytotoxicity. In vivo, NRGN silencing suppressed tumor growth and prolonged survival in a CD8⁺ T cell-dependent manner, effects reversed by β2m deletion or H-2Kb blockade. Mechanistically, NRGN downregulated IRF8 by reducing its mRNA stability through FMR1 and stabilizing FMR1 protein via inhibition of MYCBP2-mediated ubiquitination, thereby sustaining suppression of antigen presentation.
Conclusions
NRGN suppresses antigen presentation via the FMR1-IRF8-MHC-I axis, thereby impairing CD8⁺ T cell-specific effector functions and promoting immune evasion in HCC. Modulation of the NRGN-IRF8-MHC-I axis could represent a potential strategy for improving immunotherapeutic responses.