He most important targets that are typically polyubiquitinylated (Figure 4). The initial clues for the role of protein ubiquitinylation as a signal for selective autophagy came from Atg knockout mice and a few Drosophila experiments. They showed that the loss of basal autophagy inside the brain resulted in large-scale accumulation of ubiquitinylated proteins [380]. Recognition of ubiquitinylated proteins throughout autophagy is mediated by ubiquitin receptors interacting with ubiquitin noncovalently, by way of their ubiquitin-binding domains. p62/SQSMT1 (hereafter p62), the very first protein reported to have such an adaptor function [41], was initially discovered as a scaffold in signaling pathways regulating cell development and proliferation; having said that, it was also detected in ubiquitinylated protein aggregates [42] (Figure 4). p62 possesses a C-terminal ubiquitin-binding domain (UBA) [43] in addition to a short LIR (LC3-interacting region) sequence responsible for LC3 interaction [41]. In addition, it features a PB1 domain promoting self-aggregation and association with other adaptors including NBR1, neighbour of BRCA1 gene 1 [15] (Figure five). Knockout studies in mice and Drosophila revealed that p62 is essential for the aggregation of ubiquitinylated proteins and thus plays important roles for their autophagic clearance [44, 45]. The levels of p62 typically inversely correlate with autophagic degradation, as the loss of Atg genes or variables required for the fusion of autophagosomes with lysosomes all result in a marked boost of p62-positive aggregates [46, 47]. p62 may also PPARĪ³ Activator Accession deliver ubiquitinylated cargos towards the proteasome, despite the fact that they may be mostly degraded by autophagy [48, 49]. An additional adaptor utilized in selective autophagy will be the abovementioned NBR1, which, via its own PB1 domain, is capable to interact with p62, and through its own UBA domain and LIR it may participate in the recruitment and autophagosomal degradation of ubiquitinylated proteins [50]. In plants, a functional hybrid homologue of p62 and NBR1 (NBR1 in PPARĪ± Agonist Accession Arabidopsis, Joka2 in tobacco) plays an important function in the disposal of polyubiquitinylated proteins accumulated under abiotic stress circumstances [51, 52]. Optineurin and NDP52 have been not too long ago described as xenophagy receptors, using the autophagic machinery for restriction of ubiquitinylated intracellular pathogens [53]. Both of them also participate in the clearance of proteinBioMed Study InternationalRIPAtg8/LC3 family members proteinsProtein Ub Ub UbUbpPBZZTBLIRKIRUBAp62 NBRaPKCERKTRAFKeapFigure 5: Domain structure of p62 and its interacting partners. You’ll find six major domains/motifs in the p62 protein, essential for its interaction with the autophagic machinery and with signaling pathways. The N-terminal Phox and Bem1 (PB1, 21-103 aa) domain is involved in the self-oligomerization of p62 or in heterodimerization with NBR1, a protein equivalent to p62. The PB1 domain can also be accountable for the binding to atypical PKC (aPKC) or to ERK1. The central zinc finger ZZ domain (128-163 aa) as well as the TRAF6-binding domain (TB, 225-250 aa) interact together with the RIP and TRAF6 proteins, respectively, to regulate the NF-B pathway. Via the LC3-interacting area (LIR, 321345 aa) and also the C-terminal ubiquitin-associated domain (UBA, 386-440 aa), p62 hyperlinks the autophagic machinery to ubiquitinylated protein substrates to promote the selective degradation of these molecules. Finally, the Keap-interacting region (KIR, 346-359 aa) binds Keap1 top to stabilization and nuclear translocation of th.