The human-restricted oncoprotein POU5F1B enhances cell invasiveness through plasma membrane remodeling

Abstract

Evolution confers new species with distinctive biological features that can translate in either purely mechanistic speciation or novel phenotypes. Retrotransposition in the last Hominidae common ancestor of the pluripotency regulator POU5F1/OCT4 led to human POU5F1B, which promotes gastrointestinal cancer growth and metastasis through unknown mechanisms. Here, we show that POU5F1B fosters cell invasiveness by inducing plasma membrane remodeling. This ability exquisitely depends on a series of post-translational modifications. Ubiquitination of two lysine residues found exclusively in human POU5F1B results in its cytoplasmic retention, contrasting with the nuclear POU5F1. ZDHHC17-mediated S-acylation then triggers POU5F1B association with membrane nanodomains enriched in cell adhesion and signaling molecules. This is accompanied by the cell surface clustering and accelerated turnover of focal adhesion proteins, with enhanced cell invasiveness. Finally, screening for inducers of POU5F1B degradation, we found its stability to depend critically on Rho-associated protein kinases, revealing potential avenues for the treatment of POU5F1B-expressing tumors.