Systems-level organization of extracellular proteostasis

Area of Science:

• Biochemistry
• Cell Biology
• Systems Biology

Background:

• Complex organisms require extracellular protein homeostasis (proteostasis) beyond cellular limits.
• Misfolded proteins accumulating outside cells contribute to various diseases.

Purpose of the Study:

• To review the hierarchical organization of extracellular proteostasis.
• To explore the components and mechanisms involved in managing extracellular misfolded proteins.
• To discuss the implications of extracellular proteostasis failure in disease and therapeutic strategies.

Main Methods:

• Review of existing literature on extracellular proteostasis.
• Analysis of the hierarchical network structure (pericellular, tissue, systemic tiers).
• Identification of key molecular players (chaperones, proteases, vesicles, receptors, immune cells) and clearance pathways (lymphatic, glymphatic transport).

Main Results:

• Extracellular proteostasis is organized hierarchically, involving cooperation between secreted factors and clearance organs.
• Feedback mechanisms involving immune signaling and fluid transport regulate proteostasis capacity.
• Failures in this stratified defense are implicated in neurodegenerative disorders and systemic amyloidoses.

Conclusions:

• Extracellular proteostasis is an integrated, systems-level network crucial for health.
• Understanding this network reveals opportunities for combinatorial and preventive therapies targeting protein misfolding diseases.
• Strategies include stabilizing proteins, enhancing clearance, and improving fluid transport.