The host ubiquitination system dynamically regulates the inflammatory response of macrophages to bacteria.

Resistant bacterial infections have become a major global public health challenge, claiming millions of lives annually and imposing enormous economic burdens. The core issue lies in the imbalance of the host immune system, particularly macrophage function. This review elucidates the pivotal role of the host ubiquitin system in macrophage antimicrobial immunity. It systematically examines how this system leverages its unique enzyme-substrate network to orchestrate immune responses with dynamic equilibrium and precision, achieved through two critical pathways: the appropriate modulation of inflammatory signaling and the targeted clearance of intracellular pathogens. Within the Toll-like receptor (TLR)/Nuclear factor kappa-B (NF-κB) pathway, the ubiquitination system initiates inflammatory responses by activating molecules such as TRAF6, while undergoing negative feedback regulation via deubiquitinating enzymes like A20 to prevent excessive inflammatory damage. Within the autophagy pathway, ubiquitination functions as a "targeting system," where ubiquitin ligases like Parkin and RNF213 mark and eliminate intracellular bacteria such as (Mtb) and Salmonella. In-depth analysis of the ubiquitin system's specific roles in infection immunity and distinct bacterial infections holds significant importance for elucidating the molecular mechanisms underlying host-pathogen interactions. It will also provide key targets and novel perspectives for developing novel therapeutic strategies against drug-resistant bacterial infections.