Human SRP Subunits Coordinate Protein Targeting and mRNA Quality Control

The Signal Recognition Particle (SRP) targets secretory proteins to the endoplasmic reticulum (ER) for their subsequent transport and protects their mRNAs from degradation by the RAPP pathway. The SRP is an RNA-protein complex consisting of six protein subunits and one noncoding RNA assembled into S- and Alu-domains. However, the distinct roles of individual SRP subunits remain undetermined. Using a molecular dissection of the human SRP through the depletion of specific subunits, we demonstrate that S-domain subunits have a primary role in mRNA protection and protein targeting, while Alu-domain subunits are dispensable. The SRP54 subunit is essential for both processes and ribosome association, while other S-domain subunits (SRP19, SRP68, and SRP72) serve supportive roles. The expression of SRP subunits is dependent on each other within the same domains, suggesting independent domain assembly. These data provide new insights into the multidomain organization and distinct functions of human SRP subunits and establish a framework for understanding the molecular mechanisms of SRP-related human diseases.