Unveiling the post-translational landscape of Claudins: Orchestrators of barrier integrity, signaling, and disease through dynamic modifications.

Claudins are a core family of transmembrane proteins that constitute tight junctions. By interacting with other tight junction proteins, they build the cellular barrier. Claudin proteins are subject to multi-tiered regulation at the pre-transcriptional, transcriptional, and post-translational levels. Post-translational modifications (PTMs) of claudins play pivotal roles in regulating paracellular permeability, barrier function, cell migration, and disease progression. This review systematically summarizes the types of PTMs on claudin proteins, including phosphorylation, ubiquitination, palmitoylation, and other PTMs, and elucidates the interplay between different PTMs. This intricate crosstalk coordinates a multilayered regulatory network that governs cellular homeostasis and disease-associated barrier dysfunction. Furthermore, we discuss the potential clinical implications of therapeutically targeting claudin PTMs or modulating their upstream and downstream regulatory molecules.