9if9

Structural highlights

Function

PELI1_HUMAN E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins (PubMed:12496252, PubMed:17675297, PubMed:29883609, PubMed:30952868). Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6 (PubMed:12496252, PubMed:17675297). Acts as a positive regulator of inflammatory response in microglia through activation of NF-kappa-B and MAP kinase (By similarity). Mediates 'Lys-63'-linked polyubiquitination of IRAK1 allowing subsequent NF-kappa-B activation (PubMed:12496252, PubMed:17675297). Conjugates 'Lys-63'-linked ubiquitin chains to the adapter protein ASC/PYCARD, which in turn is crucial for NLRP3 inflammasome activation (PubMed:34706239). Mediates 'Lys-48'-linked polyubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation; preferentially recognizes and mediates the degradation of the 'Thr-182' phosphorylated form of RIPK3 (PubMed:29883609). Negatively regulates necroptosis by reducing RIPK3 expression (PubMed:29883609). Mediates 'Lys-63'-linked ubiquitination of RIPK1 (PubMed:29883609). Following phosphorylation by ATM, catalyzes 'Lys-63'-linked ubiquitination of NBN, promoting DNA repair via homologous recombination (PubMed:30952868). Negatively regulates activation of the metabolic mTORC1 signaling pathway by mediating 'Lys-63'-linked ubiquitination of mTORC1-inhibitory protein TSC1 and thereby promoting TSC1/TSC2 complex stability (PubMed:33215753).[UniProtKB:Q8C669]^{[1] [2] [3] [4] [5]}

References

1. ↑ Jiang Z, Johnson HJ, Nie H, Qin J, Bird TA, Li X. Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex. J Biol Chem. 2003 Mar 28;278(13):10952-6. PMID:12496252 doi:10.1074/jbc.M212112200
2. ↑ Butler MP, Hanly JA, Moynagh PN. Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases. J Biol Chem. 2007 Oct 12;282(41):29729-37. Epub 2007 Aug 3. PMID:17675297 doi:http://dx.doi.org/10.1074/jbc.M704558200
3. ↑ Choi SW, Park HH, Kim S, Chung JM, Noh HJ, Kim SK, Song HK, Lee CW, Morgan MJ, Kang HC, Kim YS. PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation. Mol Cell. 2018 Jun 7;70(5):920-935.e7. PMID:29883609 doi:10.1016/j.molcel.2018.05.016
4. ↑ Ha GH, Ji JH, Chae S, Park J, Kim S, Lee JK, Kim Y, Min S, Park JM, Kang TH, Lee H, Cho H, Lee CW. Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks. Nat Commun. 2019 Apr 5;10(1):1577. PMID:30952868 doi:10.1038/s41467-019-09641-9
5. ↑ Ko CJ, Zhang L, Jie Z, Zhu L, Zhou X, Xie X, Gao T, Yang JY, Cheng X, Sun SC. The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses. EMBO J. 2021 Jan 15;40(2):e104532. PMID:33215753 doi:10.15252/embj.2020104532