Bacterial EPIYA/EPIYA-like effector motifs and host regulatory pY-SH2 logic: a sequence-informed three-layer convergence model.

Bacterial pathogens frequently manipulate host signaling through short linear motifs (SLiMs) that are compact, rapidly evolvable, and often embedded in flexible effector regions. EPIYA/EPIYA-like effector motifs and related bacterial phosphotyrosine (pY) modules are prominent examples because they can be phosphorylated by host tyrosine kinases and subsequently interpreted by host SH2-domain-containing proteins. Here, we develop a sequence-informed and literature-integrated three-layer convergence model in which bacterial EPIYA/EPIYA-like and related pY effector motifs may converge toward the regulatory pY-SH2 logic represented by host ITIM and ITSM motifs. The proposed convergence occurs at three interconnected levels: local Tyr-centered sequence grammar, compatibility with host tyrosine-kinase writing, and SH2-reader recognition. This model does not imply that bacterial motifs are canonical ITIMs or ITSMs, nor does it imply direct homology or functional equivalence. Instead, host ITIM and ITSM motifs are used as reference models for regulatory pY-SH2 docking, whereas bacterial effectors such as CagA, BepD, and Tir illustrate how pathogens can install ectopic pY-centered signaling interfaces. A pLogo-based Tyr-centered comparison provides the sequence-level entry point for this model by visualizing shared Tyr0-centered organization and class-specific flanking-residue patterns among EPIYA/EPIYA-like, ITIM, and ITSM motifs. By shifting the comparison from motif identity to kinase writability and SH2-reader compatibility, this Perspective provides a framework for understanding how bacterial effectors evolve host-readable pY signaling modules.