DNAJs: more than substrate delivery to HSPA

Area of Science:

• Molecular and Cellular Biology
• Biochemistry
• Protein Homeostasis

Background:

• Proteins are vital for cellular functions but susceptible to environmental stress (e.g., heat, redox changes) leading to misfolding and aggregation.
• Cells possess intricate protein quality control (PQC) networks to manage proteotoxic stress.
• The PQC network comprises interconnected degradation and refolding pathways that share components and substrate affinities.

Purpose of the Study:

• To elucidate the interdependencies between protein degradation and refolding pathways within the PQC network.
• To explain how cellular mechanisms determine the fate of misfolded or aggregated proteins.
• To highlight the specific roles of ubiquitylation and Hsp70 co-chaperones (DNAJ class) in substrate processing.

Main Methods:

• Review and synthesis of existing literature on protein quality control mechanisms.
• Focus on ubiquitylation as a key signaling event.
• Analysis of the function of Hsp70 co-chaperones in substrate triage.

Main Results:

• Demonstration of shared components and overlapping substrate affinities between protein folding and degradation pathways.
• Illustration of how ubiquitylation and Hsp70 co-chaperones integrate signals to direct proteins towards refolding or degradation.
• Examples of substrate fate determination within the complex PQC network.

Conclusions:

• The protein quality control network is a highly integrated system where degradation and refolding pathways are intertwined.
• Ubiquitylation and Hsp70 co-chaperones play critical roles in orchestrating the cellular response to protein stress.
• Understanding these mechanisms is crucial for comprehending cellular resilience and disease pathogenesis.