Actin-related ACTL8 localizes to the nucleus and modulates locus-specific transcription through chromatin regulation

Actin-related proteins (Arps) are evolutionarily ancient and broadly expressed, yet some Arps evolved in mammals and acquired germline-specific expression. Here, we investigate the germline-specific Arp “Actin-like 8” (ACTL8), which is also misexpressed in multiple cancers with unexplored molecular roles. We show that ACTL8 surprisingly localizes to the nucleus of spermatogonia in human testes and breast and lung cancer cells. In breast cancer cells, ACTL8 misexpression alters transcriptional programs primarily in cell migration pathways, and ACTL8 depletion increases migration rate. Mechanistically, we find that ACTL8 interacts with KDM5B, an H3K4 demethylase and transcriptional repressor, and demonstrate that this interaction contributes to changes in migration. Consistent with this, ACTL8 loss increases H3K4me3 at genes associated with migration, indicating transcriptional activation. These findings establish ACTL8 as a novel nuclear Arp that plays a role in KDM5B-mediated transcriptional repression, providing insight into its function in chromatin regulation in cancer and potentially spermatogenesis.