ARIES domains: functional signaling units of type I interferon responses

The innate immune system relies on a network of signaling proteins classified by shared domains, which serve as functional units that orchestrate inflammatory and host defensive activities. Within type I interferon (IFN) responses, the stimulator of interferon genes protein (STING), mitochondrial antiviral-signaling protein (MAVS), Toll-IL-1 receptor-resistance protein domain-containing adapter-inducing interferon-β (TRIF), Toll-like receptor adapter interacting with SLC15A4 on the lysosome (TASL), insulin receptor tyrosine kinase substrate protein of 53 kDa (IRSp53), and GEM interacting protein (GMIP) utilize a conserved pLxIS motif to recruit IRF family transcription factors. Notably, the pLxIS motif functions within a larger signaling unit, which is referred to here as an Activator of Interferon Expression via a pLxIS motif (ARIES) domain. ARIES domains consist of the pLxIS motif and adjacent kinase activation motifs that together drive IFN responses. This review explores how ARIES domains promote immune responses via shared and distinct signaling mechanisms, protein localization, and regulation of metabolic shifts, underscoring their evolutionary conservation and critical role in host defense.