Sqstm1 Conditional Knockout mouse models

p62, the product of mouse Sqstm1 and ortholog of human SQSTM1, is a multidomain signaling adaptor and selective autophagy receptor built from an N-terminal PB1 domain that self-oligomerizes and binds NBR1 and atypical PKCs, a ZZ zinc finger, a TRAF6 binding region, an LC3-interacting region, a KEAP1-interacting region, and a C-terminal UBA domain that captures ubiquitinated cargo. By bridging polyubiquitinated substrates to LC3 on the phagophore, p62 drives aggrephagy and mitophagy, while sequestering KEAP1 to activate NRF2 antioxidant transcription and scaffolding NF-kappaB signaling. SQSTM1 mutations, mostly clustered in the UBA domain, cause Paget disease of bone, ALS with frontotemporal dementia, and distal myopathy. Constitutive knockout mice are viable but develop mature-onset obesity, insulin resistance, and age-dependent neurodegeneration, so metabolic confounds argue for conditional deletion with neuronal or microglial Cre drivers, while UBA or LIR point knockins cleanly separate cargo binding from NRF2 and NF-kappaB functions.

Tissue restricted knockout of Sqstm1 keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.