Sequestosome

Sequestosome is a cytoplasmic inclusion formed in response to cellular stress that functions to sequester polyubiquitinated proteins for degradation by autophagy. The term often refers to p62 bodies, which are largely composed of the autophagy receptor p62/SQSTM1 (sequestosome 1).

p62 contains several domains: a PB1 domain that mediates self-oligomerization, a ubiquitin-associated (UBA) domain that binds polyubiquitin chains, and a LC3-interacting region (LIR) that connects cargo to the autophagosome via LC3. Through these interactions, p62 links ubiquitinated substrates to the autophagy machinery. Additional receptors such as NBR1 and OPTN can participate in cargo recognition.

Sequestosomes form by phase separation and are dynamic structures; they enlarge when autophagy is inhibited and tend to dissolve when autophagic flux resumes.

Functionally, they contribute to selective autophagy (aggrephagy), facilitating clearance of misfolded proteins and damaged organelles; p62 can also influence signaling pathways, including KEAP1–NRF2 and NF‑κB, linking proteostasis to cellular stress responses.

Clinical significance: p62-containing inclusions accumulate in several neurodegenerative disorders where autophagy is compromised, such as Alzheimer's disease, Parkinson's disease, and ALS/FTD. Mutations in SQSTM1 cause Paget disease of bone type 4 and can be associated with motor neuron disease. Due to its role as an autophagy adaptor, p62 levels and the presence of sequestosome-like structures are used as indicators of autophagic flux in research and pathology.

See also: autophagy, ubiquitin-proteasome system, SQSTM1.