Decipher the Organization of a Multilayered Cellular Quality Control Network - PROJECT SUMMARY/ABSTRACT In many types of human diseases, pathogenesis can be attributed to impaired structure or function of biomacromolecules, including biomolecules, macromolecular complexes, and organelles. In eukaryotic cells, mechanisms of maintaining their integrity at the molecular/cellular level is known as quality control pathways, which monitor and repair damage to biological entities. Interference of the quality control pathways has been linked to the pathogenesis and pathophysiology of a wide spectrum of human diseases. Intriguingly, pathological hallmarks caused by quality control defects, such as aggregation of defective proteins and damaged organelles, often co-occur in many human diseases, suggesting that different quality control pathways may interact and assemble a network in response to diverse type of cellular stress. However, whether and how they interact remains a mystery. The ambiguity in our knowledge of the mechanisms by which they interact has significantly limited our understanding of the role of quality control pathways in pathogenesis, as well as our options for simultaneously mitigating both pathological abnormalities in disease interventions. My long-term goal is to understand the biology of different quality control systems, how they cooperate to maintain cell/tissue integrity, and how their deficiencies contribute to the pathogenesis of human diseases. Currently, most research focuses on the role of a single quality control system, and little is known about how different systems cooperate with each other. My previous work has demonstrated that when faced with mitochondrial stress, RQC (ribosome-associated protein quality control) targets the translational arrest of a specific group of mitochondrial proteins encoded by the nuclear genome. RQC generates CTEs (carboxyl-terminus extensions) on nascent peptide chains in a 40S/mRNA template-independent manner. CTE-modified mitochondrial proteins severely impair mitochondrial function, potentially linking RQC to MQC (mitochondrial quality control). I have further adopted new methodologies to assess the efficiency of different quality control systems and developed novel animal models that pave the way for analyzing the communication between quality control pathways. In unpublished work, we found evidence that split ribosomal subunits from stalled translation machinery have unique and critical roles in linking different levels of quality controls pathways, and in coordination with other cellular signaling pathways. For the next 5-year period, my lab will focus on dissecting their molecular basis. The questions we ask are, what signaling pathways connect and regulate, or can be connected and regulated by stalled/dissociated ribosomal subunits, during stress response. The answer to these questions will fill gaps in our knowledge of a fundamental biological concept, namely how cells mobilize different quality control pathways in response to various stresses. They will also gain insights into how dysregulation of quality control mechanisms simultaneously contributes to the development of co-occurring pathological features in disease pathogenesis.
