Career: quality control during ribosome assembly

The National Science Foundation Division of Molecular and Cellular Biosciences awarded $886,687 to the Stowers Institute for Medical Research on July 15, 2026, under the Biological Sciences program (CFDA 47.074) to investigate molecular mechanisms of quality control during ribosome assembly.

The research defines how cells detect and eliminate defective ribosome assembly intermediates through the ribosome assembly surveillance pathway (RASP), focusing on selective recognition of faulty ribosomes and their targeted destruction. The work centers on a scaffold protein hypothesized to bind defective ribosomes and recruit downstream degradation machinery. The project combines fundamental molecular and structural analysis with educational outreach, training undergraduate students through hands-on research and bringing biology instruction into Kansas City public schools using zebrafish as a model organism.

Performance occurs in Kansas City, Missouri, with work spanning the five-year period of performance from award date through June 30, 2031. This is a Project Grant under the Biological Sciences program, which supports basic research to strengthen the Nation's scientific enterprise and advance understanding of major biological problems. The findings are positioned to improve human health by explaining complex diseases such as cancer.

Abstract

Proteins are molecules that build our bodies, help chemical reactions happen, and allow cells to communicate. All proteins are produced by tiny machines inside cells called ribosomes. To grow, adapt, fight off infections, and repair wounds, our bodies need to produce a huge number of ribosomes every day. However, if mistakes are made during this process, a defective ribosome can be produced. When broken ribosomes build up, they can disrupt protein production and cause disease. Although ribosomes are very important, how cells find and remove faulty ones remains unknown. This research will help to understand how cells keep ribosomes working properly. The findings could improve human health by helping explain complex diseases, such as cancer. The project will also train undergraduate students through hands-on research. This experience will help them gain skills for careers in biotechnology and medicine. In addition, IT will bring science into kansas city public schools. Students will learn biology through hands-on activities using zebrafish. By combining research with education, this project supports scientific discovery, prepares future scientists, and helps more people engage with science. This project advances NSF?s priorities in biotechnology. This project will define the molecular mechanisms by which cells detect and eliminate defective ribosome assembly intermediates through a recently discovered pathway, termed the ribosome assembly surveillance pathway (rasp). Preliminary studies demonstrate that aberrant pre-ribosomes are rapidly recognized and degraded, yet the molecular basis of this process remains unclear. The proposed work focuses on two key activities within this pathway: the selective recognition of faulty ribosomes and their targeted destruction. A central component is a scaffold protein that binds defective ribosomes and is hypothesized to recruit downstream degradation machinery. Using structure-function analysis and quantitative proteomics, this project will determine how this factor distinguishes aberrant from normal ribosomes and coordinates the assembly of degradation complexes. In parallel, the project will define how defective ribosomal components are selectively marked for degradation through ubiquitination, using DI-GLY proteomics and biochemical approaches to identify key substrates and regulatory mechanisms. These molecular insights will be extended to an organismal context by investigating how disruption of ribosome quality control impacts tissue development in zebrafish, with a focus on cartilage formation. By integrating genome engineering, quantitative mass spectrometry, and structural approaches, this work will establish a mechanistic framework for ribosome quality control and reveal how its failure leads to developmental defects. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.- subawards are planned for this award.