Wednesday, February 5, 2025
2/5/2025
Project Summary The oncoprotein interferon regulatory factor 4 (IRF4) is a lymphocyte-specific transcription factor that is frequently overexpressed and mutated in hematological malignancies, including Epstein-Barr Virus (EBV)- associated, AIDS-related lymphomas (ARLs), which are the leading cause of HIV/AIDS-related cancer deaths even in the current antiretroviral therapy (ART) era. However, the precise mechanisms underlying IRF4- mediated oncogenesis is poorly understood. We have shown that IRF4 is critical for survival of virus (EBV, HTLV1)-transformed cells, and its depletion causes apoptosis, at least through transcriptional upregulation of the oncogenic miRNA miR-155 and the adaptor protein LIMD1 that in turn participates in EBV Latent Transmembrane Protein 1 (LMP1) signal transduction and is required for oxidative stress-induced autophagy, amongst many other IRF4 transcriptional targets. We have also shown that IRF4 is activated through c-Src- mediated tyrosine phosphorylation downstream of LMP1 signaling, in EBV-transformed cells, with the aid of several unbiased “state-of-the-art” high throughput techniques including phosphotyrosine proteomics, and ubiquitinomics. Furthermore, we have collected several lines of evidence in these studies showing that IRF4 is ubiquitinated with K63-linked ubiquitin chains, and that apoptosis induces a smaller size of IRF4, which may be a caspase-cleaved product and may represent a dominant negative mutant lacking the DNA-binding activity. Correspondingly, a potential caspase-cleavage site proximal to C-terminus of its DNA-binding domain was identified. Thus, the proposed study aims to test two hypotheses that: and converts IRF4 to a dominant-negative pro-apoptotic mutant; and 1) 2) caspase-3 cleaves IRF4 in apoptosis LMP1 signaling stimulates K63-linked ubiquitination of IRF4 that promotes IRF4 transcriptional activity. These studies will provide novel mechanistic insights into IRF4 posttranslational modifications in regulation of its activity and functions in virus-associated hematological malignancies. Findings from these studies and future long-term pursuits will shed new light on the importance of IRF4 in viral oncogenesis, and may identify the LMP1-IRF4 regulatory network as a potential therapeutic target for treating EBV-associated, AIDS-related hematological malignancies.
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