Systems-level organization of extracellular proteostasis
Summary
One defining feature of complex organisms is the ability to maintain protein homeostasis beyond cellular boundaries. We review how extracellular proteostasis is organized as a hierarchical network spanning pericellular, tissue, and systemic tiers. At each tier, secreted chaperones, proteases, vesicles, receptors, immune sentinels, and clearance organs cooperate to recognize, buffer, and eliminate misfolded proteins. Feedback through immune signaling, stress-induced protein secretion, and g
Content
# Systems-level organization of extracellular proteostasis
*Published: 2026 Mar 26*
One defining feature of complex organisms is the ability to maintain protein
homeostasis beyond cellular boundaries. We review how extracellular proteostasis
is organized as a hierarchical network spanning pericellular, tissue, and
systemic tiers. At each tier, secreted chaperones, proteases, vesicles,
receptors, immune sentinels, and clearance organs cooperate to recognize,
buffer, and eliminate misfolded proteins. Feedback through immune signaling,
stress-induced protein secretion, and glymphatic and lymphatic transport adjusts
capacity to proteotoxic load. We illustrate how failures in this stratified
defense underlie neurodegenerative disorders and systemic amyloidoses, and we
highlight strategies that stabilize extracellular proteins, augment clearance
pathways, or enhance fluid transport. Viewing extracellular proteostasis as an
integrated systems-level network reveals opportunities for combinatorial and
preventive therapies.
DOI: 10.1126/science.aed3712