Dhiman, Asmita and Talukdar, Sharmila and Chaubey, Gaurav Kumar and Dilawari, Rahul and Modanwal, Radheshyam and Chaudhary, Surbhi and Patidar, Anil and Boradia, Vishant Mahendra and Kumbhar, Pradeep and Raje, Chaaya Iyengar and Raje, Manoj (2023) Regulation of macrophage cell surface GAPDH alters LL-37 internalization and downstream effects in the cell. Journal of Innate Immunity .
Full text not available from this repository. (Request a copy)Abstract
Mycobacterium tuberculosis (M.tb), the major causative agent of tuberculosis (TB), has evolved mechanisms to evade host defenses and persist within host cells. Host directed therapies (HDTs) against infected cells are emerging as an effective option. Cationic host defense peptide LL-37 is known to internalize into cells and induce autophagy resulting in intracellular killing of M.tb. This peptide also regulates the immune system and interacts with the multifunctional protein Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), inside macrophages. Our investigations revealed that GAPDH moonlights as a mononuclear cell surface receptor that internalizes LL-37. We confirmed that the surface levels of P2X7, the receptor previously reported for this peptide remained unaltered on M.tb infected macrophages. Upon infection or cellular activation with IFNγ, surface recruited GAPDH bound to and internalized LL-37 into endocytic compartments via a lipid raft dependent process. We also discovered a role for GAPDH in LL-37 mediated autophagy induction and clearance of intracellular pathogen. In infected macrophages wherein GAPDH had been knocked down, we observed an inhibition of LL-37 mediated autophagy which was rescued by GAPDH over expression. This process was dependent on intracellular calcium and P38 MAPK pathways. Our findings reveal a previously unknown process by which macrophages internalize an antimicrobial peptide via cell surface GAPDH and suggests a moonlighting role of GAPDH in regulating cellular phenotypic responses of LL-37 resulting in reduction of M.tb burden.
| Item Type: | Article |
|---|---|
| Additional Information: | The copyright of this article belongs to Karger Publisher |
| Subjects: | Q Science > QR Microbiology |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 07 Jun 2023 07:49 |
| Last Modified: | 07 Jun 2023 07:49 |
| URI: | http://crdd.osdd.net/open/id/eprint/3081 |
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