Recombinant Human SQSTM1 / p62 protein (GST tag N-Terminus)

Specifications

Form

Liquid

General info

Function

Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes (PubMed : 15340068, PubMed : 15953362, PubMed : 16286508, PubMed : 17580304, PubMed : 20168092, PubMed : 22017874, PubMed : 22622177, PubMed : 24128730, PubMed : 28404643, PubMed : 29343546, PubMed : 29507397, PubMed : 31857589, PubMed : 33509017, PubMed : 34471133, PubMed : 34893540, PubMed : 35831301, PubMed : 37306101, PubMed : 37802024). Promotes the recruitment of ubiquitinated cargo proteins to autophagosomes via multiple domains that bridge proteins and organelles in different steps (PubMed : 16286508, PubMed : 20168092, PubMed : 22622177, PubMed : 24128730, PubMed : 28404643, PubMed : 29343546, PubMed : 29507397, PubMed : 34893540, PubMed : 37802024). SQSTM1 first mediates the assembly and removal of ubiquitinated proteins by undergoing liquid-liquid phase separation upon binding to ubiquitinated proteins via its UBA domain, leading to the formation of insoluble cytoplasmic inclusions, known as p62 bodies (PubMed : 15911346, PubMed : 20168092, PubMed : 22017874, PubMed : 24128730, PubMed : 29343546, PubMed : 29507397, PubMed : 31857589, PubMed : 37802024). SQSTM1 then interacts with ATG8 family proteins on autophagosomes via its LIR motif, leading to p62 body recruitment to autophagosomes, followed by autophagic clearance of ubiquitinated proteins (PubMed : 16286508, PubMed : 17580304, PubMed : 20168092, PubMed : 22622177, PubMed : 24128730, PubMed : 28404643, PubMed : 37802024). SQSTM1 is itself degraded along with its ubiquitinated cargos (PubMed : 16286508, PubMed : 17580304, PubMed : 37802024). Also required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed : 20168092). Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes (PubMed : 26344566). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1 : interaction inactivates the BCR(KEAP1) complex by sequestering the complex in inclusion bodies, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed : 20452972, PubMed : 28380357, PubMed : 33393215, PubMed : 37306101). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed : 29496741). Involved in endosome organization by retaining vesicles in the perinuclear cloud : following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed : 27368102, PubMed : 33472082). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (PubMed : 25101860). May regulate the activation of NFKB1 by TNF, nerve growth factor (NGF) and interleukin-1 (PubMed : 10356400, PubMed : 10747026, PubMed : 11244088, PubMed : 12471037, PubMed : 16079148, PubMed : 19931284). May play a role in titin/TTN downstream signaling in muscle cells (PubMed : 15802564). Adapter that mediates the interaction between TRAF6 and CYLD (By similarity).

Post-translational modifications

Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer interface and increases binding affinity to ubiquitinated proteins (By similarity). Phosphorylation at Ser-407 also primes for subsequent phosphorylation at Ser-403 (By similarity). Phosphorylation at Ser-403 by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing the affinity between the UBA domain and polyubiquitin chains (PubMed:22017874, PubMed:25040165). Phosphorylation at Ser-403 by ULK1 is stimulated by SESN2 (PubMed:25040165). Phosphorylated at Ser-403 by TBK1, leading to promote relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:37306101). Phosphorylated in vitro by TTN (PubMed:15802564).. Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Ubiquitination by UBE2D2 and UBE2D3 increases its ability to bind polyubiquitin chains by destabilizing the UBA dimer interface (PubMed:28322253). Deubiquitination by USP15 releases target vesicles for fast transport into the cell periphery (PubMed:27368102). Ubiquitinated by the BCR(KEAP1) complex at Lys-420, increasing SQSTM1 sequestering activity and promoting its degradation (PubMed:28380357). Ubiquitinated via 'Lys-29' and 'Lys-33'-linked polyubiquitination leading to xenophagic targeting of bacteria and inhibition of their replication (PubMed:27880896).. Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity by destabilizing the UBA dimer interface and increases binding affinity to ubiquitinated proteins (PubMed:31857589). Deacetylated by HDAC6 (PubMed:31857589).. Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for efficient autophagic degradation of SQSTM1-cargo complexes by promoting affinity for ATG8 proteins and recruitment of p62 bodies to autophagosomes (PubMed:37802024). Dealmitoylated at Cys-289 and Cys-290 by LYPLA1 (PubMed:37802024).. (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation (PubMed:24331465). Degradation by SpeB prevents autophagy, promoting to S.pyogenes intracellular replication (PubMed:24331465).. (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1-positive structures.

Subcellular localisation

Nucleus