Cellular Strategies of Protein Quality Control-Degradation

Introduction

Maintaining the quality of all proteins in an organism is fundamental to life since it ensures tissue function, organismal health, and longevity. Protein quality control (PQC) is achieved by selective degradation of damaged proteins, limiting the formation of protein aggregates and neurodegeneration characteristic of Alzheimer’s, Huntington’s, and Parkinson’s disorders.

Role of E3 Ubiquitin Ligases

Important regulators of cellular proteolysis are E3 ubiquitin ligases that target damaged proteins for degradation. However, therapeutically relevant E3 ligases specialized for PQC degradation (PQCD) are largely unknown. PQCD of damaged proteins is a dynamic process that must be coordinated with physiological and environmental challenges to overcome stress-induced proteotoxicity.

Challenges in the Field

Despite progress in characterizing regulatory signals for protein degradation, the major challenge in this field is to understand the dynamic rewiring of PQCD pathways under acute and chronic stress conditions.

Research Goals

Thus, the overall goal of the proposed research program is to unravel the molecular basis of stress-induced PQCD, which is critical for physiological integrity and health.

Methodology

The mechanistic role of PQC-E3 ubiquitin ligases will be investigated using mammalian cell cultures and the genetic model organism Caenorhabditis elegans, which reflects many conserved human ubiquitin-dependent PQCD pathways and allows for well-defined lifespan studies.

Innovative Approach

This innovative and interdisciplinary research program will combine state-of-the-art proteome analyses with tissue-specific manipulation of stress signals and large-scale genetic studies for identification and characterization of:

1. Stress-induced PQCD
2. Aggregating damaged proteins
3. E3 ligases specialized for PQCD

Significance of the Research

Importantly, in addition to providing new molecular insights into stress-induced adaptive mechanisms, this research program will lay the foundation for exploring the pathophysiology of aggregation-related neurodegeneration triggered by chronic protein damage.