All organisms evolved strategies to protect themselves from intracellular pathogens. The processes that occur inside an infected cell are called cell-autonomous immunity, which we define as mechanisms by which a cell recognizes a pathogen and attempts to counteract it [1]. Cell-autonomous immunity works efficiently when the proteins that detect pathogens are continuously expressed and quickly transmit a signal upon binding to their ligand. The infected cell needs to destroy the pathogen before it exercises mechanisms that allow evasion from the cell-autonomous line of defense. In addition to their cell-intrinsic functions, cells evolved diverse strategies to alert neighboring cells to threats. These include the secretion of cytokines belonging to the interferon (IFN), tumor necrosis factor (TNF), and interleukin-1 (IL-1) families. In response to these signals, cells in the microenvironment can drive the expression of antimicrobial proteins, albeit comparatively slower compared with cell-intrinsic mechanisms. The fastest way for a cell to change its behavior is through immediate post-translational modification of its proteins, and ubiquitination plays a central role in cell-autonomous immunity [2].

Here, we provide examples on how ubiquitin bridges cell-autonomous immunity, focusing on the mechanisms studied in humans and mice. Additionally, we explore novel strategies to bolster ubiquitin-based signaling to fight intracellular infections.