Pellino E3 Ubiquitin Protein Ligase Family Member 2 (PELI2) is a protein encoded by the PELI2 gene in humans. This protein is part of the Pellino family of E3 ubiquitin ligases, which play a crucial role in the regulation of immune responses through the ubiquitylation of specific substrate proteins .
PELI2 is characterized by an N-terminal forkhead-associated (FHA) domain and a C-terminal RING-like domain. The FHA domain recognizes phospho-threonine residues, facilitating the association with interleukin-1 receptor-associated kinases (IRAKs), while the RING-like domain confers E3 ubiquitin ligase activity . This activity involves catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, a process essential for various cellular functions, including protein degradation, signal transduction, and DNA repair .
PELI2 is implicated in the Toll-like receptor (TLR) and interleukin-1 (IL-1) signaling pathways. It interacts with complexes containing IRAK kinases and TNF receptor-associated factor 6 (TRAF6), mediating the polyubiquitination of IRAK1. This modification is crucial for the activation of downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway . These pathways are vital for the innate immune response, leading to the production of pro-inflammatory cytokines and other immune mediators .
PELI2’s role in immune signaling highlights its importance in both innate and adaptive immunity. By regulating the ubiquitylation of key signaling proteins, PELI2 ensures the proper activation and termination of immune responses. Dysregulation of PELI2 activity has been associated with various immune-related disorders, including hyperlipoproteinemia type IV and 3MC syndrome .
Given its central role in immune signaling, PELI2 is a potential target for therapeutic interventions aimed at modulating immune responses. Research into the molecular mechanisms of PELI2 function and regulation continues to provide insights into its potential as a therapeutic target for treating immune-related diseases .