NAD+ Synthesis, Mono(ADP-Ribosyl)ation, Protein Translation, and Proteostasis in Ovarian Cancer
Abstract
The fundamental importance of ribosomes to cellular functions and broader biological outcomes is, by now, readily apparent. Recent studies have shown that the central components of the ribosome, including the repertoire of ribosomal proteins (RPs), can be regulated and diversified to control protein translation. This regulation is mediated, in part, by post-translational modifications (PTMs) of ribosomal proteins. PTMs of ribosomal proteins are versatile, may have functional consequences for translational control, and are intimately linked to human disease. In preliminary studies, we have shown that ribosome mono(ADP-ribosyl)ation (MARylation), a PTM of proteins, is dependent on the cytosolic NAD+ synthase, NMNAT-2, and the PARP monoenzyme, PARP-16, an endoplasmic-reticulum-anchored, cytosol-facing protein. In addition, our preliminary results exploring this biology have revealed that MARylation of RPs by NMNAT-2 and PARP-16: (1) attenuates protein translation and reduces protein aggregation; (2) controls loading of mRNAs onto polysomes; and (3) supports the viability of cells by promoting proteostasis. The results suggest a functional link between NAD+ production and consumption in ribosome activity. Our results suggest a model in which ribosome MARylation regulates protein synthesis to prevent protein aggregation and proteotoxic stress. In the context of ovarian cancer cells, this enhances cell growth and likely accounts for the elevated expression of NMNAT-2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1222263
Entities
People
- W. L. Kraus
Organizations
- University of Texas at Dallas