PELI1

Function

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).

Pathway

Protein modification; protein ubiquitination.

Post-translational modifications

Phosphorylation by IRAK1 and IRAK4 enhances its E3 ligase activity (PubMed:17997719). Phosphorylated by ATM in response to DNA damage, promoting localization to DNA double-strand breaks (DSBs) and ability to mediate 'Lys-63'-linked ubiquitination of NBN (PubMed:30952868).

Sumoylated.

Sequence Similarities

Belongs to the pellino family.

Tissue Specificity

Expressed at high levels in normal skin but decreased in keratinocytes from toxic epidermal necrolysis (TEN) patients (at protein level).

Cellular localization

• Chromosome
• Localizes to DNA double-strand breaks (DSBs) in response to DNA damage.

Alternative names

PRISM, PELI1, E3 ubiquitin-protein ligase pellino homolog 1, Pellino-1, Pellino-related intracellular-signaling molecule, RING-type E3 ubiquitin transferase pellino homolog 1

Database links

swissprot:Q96FA3 entrezGene:57162 entrezGene:57161 swissprot:Q9HAT8 omim:614798 omim:614797