Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity. Specifically deubiquitinates histone H2B at 'Lys- 120' (H2BK120Ub), a specific tag for epigenetic transcriptional activation and acts as a regulator of mRNA splicing (PubMed:23824326). Antagonizes DNA double-strand break-induced ubiquitination of H2AX thereby participating in the maintenance of genome integrity (PubMed:35598681). Plays a role in the negative regulation of cell proliferation through the AKT pathway by deubiquitinating FKBP51, leading to enhanced AKT1 dephosphorylation by PHLPP1 (PubMed:28363942). Also regulates the mitotic spindle checkpoint and prevents aneuploidy (PubMed:36702832). Negatively regulates cellular antiviral responses via deconjugating 'Lys-63'-linked ubiquitination of STING1 (PubMed:30943264). Significantly enhances the anti-HIV-1 activity of APOBEC3G. Mechanistically, stabilizes APOBEC3G by counteracting HIV-1 Vif-mediated APOBEC3G ubiquitination (PubMed:31397674). {ECO:0000269|PubMed:23824326, ECO:0000269|PubMed:28363942, ECO:0000269|PubMed:30943264, ECO:0000269|PubMed:31397674, ECO:0000269|PubMed:35598681, ECO:0000269|PubMed:36702832}. This is the function of USP49 (ubiquitin specific peptidase 49, ENSG00000164663).