Defective Human SRP Induces Protein Quality Control and Triggers Stress Response

Regulation of Aberrant Protein Production (RAPP) is a protein quality control in mammalian cells. RAPP degrades mRNAs of nascent proteins not able to associate with their natural interacting partners during synthesis at the ribosome. However, little is known about the molecular mechanism of the pathway, its substrates, or its specificity. The Signal Recognition Particle (SRP) is the first interacting partner for secre-tory proteins. It recognizes signal sequences of the nascent polypeptides when they are exposed from the ribosomal exit tunnel. Here, we reveal the generality of the RAPP pathway on the whole transcriptome level through depletion of human SRP54, an SRP subunit. This depletion triggers RAPP and leads to decreased expression of the mRNAs encoding a number of secretory and membrane proteins. The loss of SRP54 also leads to the dramatic upregulation of a specific network of HSP70/40/90 chaperones (HSPA1A, DNAJB1, HSP90AA1, and others), increased ribosome associated ubiquitination, and change in expression of RPS27 and RPS27L suggesting ribosome rearrangement. These results demonstrate the complex nature of defects in protein trafficking, mRNA and protein quality control, and provide better understanding of their mechanisms at the ribosome. (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecom-mons.org/licenses/by/4.0/).

Automated summary

Regulation of Aberrant Protein Production (RAPP) is a protein quality control mechanism in mammalian cells. It degrades the mRNA of nascent proteins that cannot associate with their natural interacting partners. Depletion of human SRP54, an SRP subunit, triggers RAPP and leads to decreased expression of mRNAs encoding secretory and membrane proteins. The loss of SRP54 also results in the upregulation of a specific network of HSP70/40/90 chaperones, increased ribosome-associated ubiquitination, and changes in the expression of RPS27 and RPS27L, indicating ribosome rearrangement.