Beyond adaptive immunity: Functional diversity of the type III-A CRISPR-Cas system in Mycobacterium tuberculosis

CRISPR-Cas systems are best known as prokaryotic adaptive immune pathways that defend against invading genetic elements. Mycobacterium tuberculosis (Mtb) harbors a type III-A CRISPR-Cas system that is structurally conserved yet exhibits little evidence of ongoing spacer acquisition. Nevertheless, its interference machinery remains functional, and increasing evidence suggests that this system has evolved roles beyond canonical adaptive immunity. Accumulating studies indicate that this system is deeply integrated into cellular regulatory networks by governing stress responses, metabolic adaptation, and host-pathogen interactions. Mechanistically, the Mtb type III-A CRISPR-Cas system operates through transcription-dependent target recognition and cyclic oligoadenylate (cOA)-mediated signal amplification, in which the ancillary ribonuclease Csm6 serves as a key effector. Functionally, CRISPR-associated proteins influence antibiotic susceptibility, oxidative stress resistance and host immune responses, and may even act as secreted immunomodulatory factors. In this review, we summarize current understanding of the genomic organization, regulatory mechanisms, and non-canonical functions of the Mtb type III-A CRISPR-Cas system, with particular emphasis on its emerging roles in stress adaptation and host immune regulation.