Critical Role of RPS4X in Modulating SCF Complex Formation and Cell Survival

Ribosomal proteins have long been recognized as vital components of ribosomes that are involved in protein synthesis. However, emerging evidence indicates that some ribosomal proteins exhibit extraribosomal functions. In this study, we investigated the role of the ribosomal protein S4 X-linked (RPS4X) in the regulation of the Skp1–Cullin1–F-box (SCF) ubiquitin ligase complex and apoptosis. We found that RPS4X expression interfered with SCF complex formation by disrupting the interaction between Cullin1 and Skp1. This disruption suppressed ubiquitination of multiple SCF complex substrates, including the anti-apoptotic proteins myeloid cell leukemia 1 (MCL1) and HS1-associated protein X1 (HAX1). Stabilization of MCL1 and HAX1 by RPS4X led to increased resistance of HeLa cells to doxorubicin-induced apoptosis. These findings suggest that RPS4X contributes to the regulation of protein homeostasis and apoptotic pathways by modulating SCF complex activity, providing new insights into the extraribosomal roles of ribosomal proteins.