Sequestosome-1

Sequestosome-1 (SQSTM1) is a 47.7 kDa molecular adapter protein that orchestrates selective macroautophagy by bridging polyubiquitinated cargo proteins to autophagosomes (UniProt: Q13501). It mediates cargo assembly into phase-separated p62 bodies and recruits these inclusions to autophagosomes via interaction with ATG8 family proteins, enabling autophagic clearance of misfolded proteins. SQSTM1 also activates the NFE2L2/NRF2 cytoprotective pathway and regulates endosomal organization.

SQSTM1 is linked to multiple neurodegenerative conditions including frontotemporal dementia and amyotrophic lateral sclerosis, as well as myopathy with rimmed vacuoles—all pathologies involving protein aggregation and autophagic dysfunction (UniProt: Q13501). The protein plays a central role in clearing proteotoxic aggregates across tissues.

In Alzheimer's disease brain, SQSTM1 is significantly upregulated with a mean log2 fold-change of +0.87 compared to age-matched controls in post-mortem tissue analyzed by TMT proteomics across subcellular fractions (Chaparral AD proteomics). This elevation may reflect a compensatory response to increased amyloid-β and tau aggregation, consistent with SQSTM1's role in proteostasis and aggrephagy.