Activation of the lysosomal damage response and selective autophagy: the coordinated actions of galectins, TRIM proteins, and CGAS-STING1 in providing immunity against Mycobacterium tuberculosis

Abstract

Autophagy is a crucial immune defense mechanism that controls the survival and pathogenesis of M. tb by maintaining cell physiology during stress and pathogen attack. The E3-Ub ligases (PRKN, SMURF1, and NEDD4) and autophagy receptors (SQSTM1, TAX1BP1, CALCOCO2, OPTN, and NBR1) play key roles in this process. Galectins (LGALSs), which bind to sugars and are involved in identifying damaged cell membranes caused by intracellular pathogens such as M. tb, are essential. These include LGALS3, LGALS8, and LGALS9, which respond to endomembrane damage and regulate endomembrane damage caused by toxic chemicals, protein aggregates, and intracellular pathogens, including M. tb. They also activate selective autophagy and de novo endolysosome biogenesis. LGALS3, LGALS9, and LGALS8 interact with various components to activate autophagy and repair damage, while CGAS-STING1 plays a critical role in providing immunity against M. tb by activating selective autophagy and producing type I IFNs with antimycobacterial functions. STING1 activates cGAMP-dependent autophagy which provides immunity against various pathogens. Additionally, cytoplasmic surveillance pathways activated by ds-DNA, such as inflammasomes mediated by NLRP3 and AIM2 complexes, control M. tb. Modulation of E3-Ub ligases with small regulatory molecules of LGALSs and TRIM proteins could be a novel host-based therapeutic approach for controlling TB.

Keywords:

• Autophagy
• CGAS
• E3-Ub ligase
• galectin
• STING1

Acknowledgements

SEH is a Robert Koch Fellow at the Robert Koch Institute, Germany, and the National Science Chair, Science and Engineering Research Board, Department of Science and Technology, New Delhi, India.

Author contributions

Asrar Ahmad Malik: Writing Original Draft, Conceptualization. Mohd Shariq: Writing Original Draft, Conceptualization. Javaid Ahmad Sheikh: Writing Original Draft, Conceptualization. Haleema Fayaz: Visualization, Writing - Review & Editing. Sheeba Zarin: Visualization, Writing - Review & Editing. Yashika Ahuja: Writing - Review & Editing. Anwar Alam: Writing - Review & Editing. Nasreen Z Ehtesham: Writing - Review & Editing, Supervision, Project administration, Funding acquisition. Seyed E Hasnain: Writing - Review and Editing, Supervision, Project administration, Funding acquisition.

Consent for publication

All authors have read the final version of the manuscript and agreed to its publication in Critical Reviews in Microbiology.

Disclosure statement

The authors have no relevant financial or nonfinancial interests to disclose.

Data availability statement

All the data are included in the manuscript.

Additional information

Funding

SEH and NZE were supported by Department of Biotechnology grants BT/PR39433/DRUG/134/90/2021 from Ministry of Science and Technology, Government of India, New Delhi. JAS was funded by a Start-up Research Grant from the University Grant Commission and the Department of Science and Technology Science and Engineering Research Board.