Advances and Perspectives on Mycobacterial Secretion Systems

Mycobacteria possess a uniquely complex cell envelope and rely on a diverse array of secretion systems to interact with their environment, ensure survival, and modulate host immune responses. This review provides a comprehensive overview of these secretion pathways, from the universally conserved Sec and Tat systems to the specialized ESX/type VII secretion systems, as well as lipid transporters of the MmpL family, with particular emphasis on Mycobacterium tuberculosis and other clinically relevant members of the M. tuberculosis complex and non-tuberculous mycobacteria. By integrating findings from historical literature and the most recent experimental and bioinformatic studies, we outline the genetic organization, structure, regulation, and functional interplay of these pathways. Emphasis is placed on how these systems are not isolated entities but form a highly interconnected network that coordinates protein and lipid export essential for virulence, immune modulation, and cell wall integrity. We also explore the translational potential of secreted effectors and their transport machineries, discussing their relevance as targets for therapeutic interventions, including novel inhibitors, diagnostic biomarkers, and vaccine candidates. We highlight critical knowledge gaps and propose avenues for future research, particularly those that leverage multidisciplinary approaches. By drawing connections across secretion systems and emphasizing their shared and distinct roles, this work aims to provide an integrated framework that supports both fundamental understanding and biomedical innovation in mycobacterial pathogenesis.