Due to the multitude of discovered interaction partners, the p62 interaction hub is able to integrate the signals of multiple pathways such as selective autophagy ], MAP kinase ], NF-κB ], mTORC1 ], Nrf2 ], and N-end degradation ], linking p62 to many essential biological processes, such as degradation, oxidative stress, nutrient sensing, and inflammation. p62's UBA domain is critical for the recognition of poly-ubiquitin and ubiquitinated cargo ]. In addition, it contains a long intrinsically disordered region (IDR) (168–388), which provides binding sites to various interacting partners such as LC3, KEAP1, and FIP200 via short binding motifs ]. The p62 molecule is a 440 aa protein that contains three structurally folded domains: a PB1 domain (1–102), a ZZ-domain (122–167), and a UBA ubiquitin-binding domain (389–434). This so-called autophagosome is directed to the lysosome where it fuses with the lysosomal membrane and its contents are degraded. In this process, a phagophore membrane is recruited through p62's interaction with LC3 and elongated until it encloses the cargo-p62 complex in a double-membrane vesicle. Due to its early discovery, p62 can be considered the archetypical autophagy receptor that is also involved in the targeted removal of other cargo types such as bacteria, viruses, and organelles ]. The molecular link to autophagy was established by p62's involvement in the disposal of poly-ubiquitinated aggregates via the lysosome ]. Further interaction studies revealed that p62 bridges the interaction of atypical protein kinase C (PKC) with RIP1 to activate the NF-κB pathway ]. Approximately 25 years ago, p62 was identified as a novel interaction partner of the SH2 domain of tyrosine–protein kinase Lck and subsequently cloned ]. P62/SQSTM1 (from here on p62) is a multidomain, multifunctional protein involved in autophagy and a series of signaling processes ]. fluorescence recovery after photobleaching.
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