Unveiling Cryptic Connections in Streptococcus mutans: Hidden Protein Interaction Networks, Global Posttranscriptional Gene Regulation, and Therapeutic Potential

To survive and thrive, bacteria must rapidly interpret complex sensory inputs and respond strategically. Central to this adaptability is the RNA degradosome, a crucial multi-protein complex that governs global RNA regulation. Our research on Streptococcus mutans, the dominant species associated with dental caries risk, reveals a surprising diversity of proteins interacting with the degradosome. We propose these are "moonlighting" proteins, serving as dynamic signaling or accessory factors that manipulate RNA targeting by the degradosome in real- time. This elegant system allows bacteria to efficiently and precisely coordinate cellular physiology with global posttranscriptional gene regulation. Our project employs a multidisciplinary approach, integrating genetics, advanced mass spectrometry, next-generation sequencing, cryo-electron microscopy, and innovative interspecies biofilm models. We aim to precisely map how the degradosome achieves its targeting specificity. In addition to advancing our understanding of fundamental genetics, another key objective is to exploit the degradosome as a strain-specific therapeutic target. By disrupting critical moonlighting interactions within the degradosome, it may be possible to deplete S. mutans in the oral cavity - a much-needed strategy to combat the global burden of dental caries. This work will reveal the structural and mechanistic mysteries of the S. mutans degradosome through the following three core objectives: i) unravel the role of moonlighting protein interactions and transcript targeting by the degradosome, ii) develop a mechanistic structural and biochemical model of a degradosome-substrate complex, and iii) assess the biological consequences and therapeutic potential of inhibiting protein moonlighting interactions with the S. mutans degradosome. Project Number: 1R01DE035840-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Justin Merritt | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $634,041 | Activity Code: R01 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11341049