SH3RF1 is a multidomain E3 ubiquitin ligase and scaffold protein with emerging roles in both microbial defense and disease pathogenesis. Primary function: SH3RF1 contains a RING domain conferring E3 ligase activity and functions as a MAP kinase scaffold protein involved in JNK signaling pathway regulation 1. Its RING domain is essential for targeting HIV-1 Gag to the plasma membrane during viral infection. Mechanism: SH3RF1 executes its functions through protein ubiquitination and scaffold-mediated signaling, influencing cell survival pathways and negatively regulating apoptosis 21. Disease relevance: Genetic variants in SH3RF1 associate with multiple disorders. A genome-wide significant SNP (rs2706748) associates with lung cancer susceptibility and interacts with smoking status 3. SH3RF1 is upregulated in diabetic kidney disease and cognitive dysfunction, suggesting involvement in apoptotic pathways underlying these comorbidities 1. The gene appears in ALS spinal cord transcriptomes as a potential risk locus affecting motor neuron disease 4. Sleep duration variants near SH3RF1 show pleiotropic associations with cardiovascular and neuropsychiatric traits 5. Clinical significance: SH3RF1 elevated expression correlates with improved prognosis in LKB1-mutant lung adenocarcinoma patients 2, suggesting potential as a prognostic biomarker and therapeutic target in specific cancer contexts.