Sequestosome 1 (p62/SQSTM1) is a multifunctional scaffold protein that serves as the primary autophagy receptor for selective degradation of ubiquitinated protein aggregates. p62 bridges ubiquitinated cargo to LC3 on autophagosomal membranes, enabling the clearance of protein aggregates, damaged organelles, and pathogens through autophagy.[1][2]
In neurodegenerative diseases, p62 accumulation in protein inclusions is a pathological hallmark, indicating impaired autophagic clearance. p62 is found in Alzheimer's disease neurofibrillary tangles, Parkinson's disease Lewy bodies, and ALS/FTD inclusions. Mutations in SQSTM1 cause familial Paget disease and are associated with ALS/FTD.[3]
p62 contains multiple interaction domains that enable its scaffold function:
PB1 Domain (N-terminal, 1-122): Mediates self-oligomerization through front-to-back interactions. Enables p62 to form helical filaments and phase-separated condensates that concentrate cargo for autophagy.
ZZ Zinc Finger Domain (122-195): Binds to NEMO and RIPK1, linking p62 to NF-κB signaling.
TB Domain (195-255): Involved in TRAF6 binding and NF-κB activation.
LIR Motif (LC3-Interacting Region, 321-342): The critical sequence (DDDWTHL) that binds to LC3/GABARAP family proteins on autophagosomal membranes. Phosphorylation of S403 and S405 enhances LC3 binding affinity.
KEAP1-Interacting Region (KIR, 347-356): Binds to KEAP1, competing with NRF2 and activating antioxidant responses.
UBA Domain (C-terminal, 386-440): Ubiquitin-associated domain that binds polyubiquitin chains (preferentially K63-linked and K48-linked) on cargo proteins.[4]
p62 undergoes liquid-liquid phase separation (LLPS) when it binds ubiquitinated proteins. The PB1-mediated oligomerization and UBA-ubiquitin interactions drive the formation of p62 condensates that recruit autophagy machinery. This process is enhanced by:[5]
p62 is the primary autophagy receptor for aggregate clearance:
Beyond autophagy, p62 regulates multiple signaling pathways:
In Alzheimer's disease, p62 pathology is prominent:
Reduced p62 expression accelerates tau pathology in mouse models, while p62 overexpression is protective.
p62/SQSTM1 mutations are directly linked to neurodegeneration:
Common SQSTM1 mutations in ALS include:
p62 accumulation activates NRF2 through KEAP1 sequestration:
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Lee & Coughlin, p62 in protein aggregation and disease (2020). 2020. ↩︎
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Zaffagnini G, et al. p62 filaments capture and present ubiquitinated cargos for autophagic degradation. J Cell Biol. 2018. ↩︎
Kirkin V, et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009. ↩︎
Salminen A, et al. Impaired autophagy and accumulation of protein aggregates in the elderly: a lesson from the SQSTM1/p62 gene. Aging Cell. 2011. ↩︎
Denton D, et al. Autophagy: a cellular and immune response against neurodegeneration. Immunity. 2015. ↩︎
Teyssou E, et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol. 2013. ↩︎
Jiang T, et al. p62 links autophagy and Nrf2 signaling. Free Radic Biol Med. 2015. ↩︎