CYTH2 (cytohesin 2) functions as a guanine-nucleotide exchange factor (GEF) that activates ARF family GTPases, particularly ARF1, ARF3, and ARF6, by promoting GDP-to-GTP exchange 1. The protein localizes to plasma membrane and cytoplasm, where it plays critical roles in multiple cellular processes. CYTH2 directly interacts with actinin-1 through its C-terminal polybasic region to regulate neurite extension in neuronal cells, with knockdown studies demonstrating its requirement for proper Arf6 activation and neurite outgrowth 2. In pathogen interactions, CYTH2 is essential for early-stage influenza virus infection by mediating endosomal trafficking, making it a potential antiviral drug target 3. The protein also facilitates Salmonella pathogenesis through the Arf6/Cyth2/Arf1 pathway, regulating actin polymerization and membrane ruffling during bacterial invasion 45. In inflammatory responses, CYTH2 (ARNO) directly binds MYD88 and activates ARF6 downstream of IL-1β signaling, disrupting endothelial barrier function independently of NF-κB pathways 1. CYTH2 is also implicated in cancer, being upregulated in hepatocellular carcinoma and serving as a methylation biomarker for Lynch syndrome-associated colorectal and endometrial cancers 67.