Mutual Regulation Between Metal Ions and Secretion Systems in Gram-Negative Bacteria: Insights into Mechanisms and Functions

Gram-negative bacteria employ multiple secretion systems (such as T1SS, T2SS, T3SS, T6SS, etc.) to secrete and transport virulence factors, thereby overcoming their complex outer membrane barriers and host immune pressures. Metal ions such as Fe, Zn, Mg, and Ca play pivotal roles in bacterial growth, metabolism, and pathogenicity. These metal ions not only function as cofactors that maintain the structural stability of secretion systems components and support energy-dependent secretion processes, but also finely regulate the expression and function of secretion systems through multiple layers, including transcriptional modulation, which is primarily executed by dedicated metal-sensing proteins such as Fur, Zur, and PhoPQ. Concurrently, secretion systems exert feedback regulation over metal ion acquisition, such as iron transporter secretion and T6SS-mediated metal ion plundering, as well as detoxification processed including metal ion efflux systems. This review comprehensively summarizes the bidirectional crosstalk between metal ions and Gram-negative bacterial secretion systems, with a focus on dissecting their regulatory patterns, physiological functions, and translational application prospects.