Regulation of Macrophage Cell Surface GAPDH Alters LL-37 Internalization and Downstream Effects in the Cell

Asmita Dhiman, Sharmila Talukdar, Gaurav Kumar Chaubey, Rahul Dilawari, Radheshyam Modanwal, Surbhi Chaudhary, Anil Patidar, Vishant Mahendra Boradia, Pradeep Kumbhar, Chaaya Iyengar Raje, Manoj Raje

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Mycobacterium tuberculosis (M.tb), the major causative agent of tuberculosis, has evolved mechanisms to evade host defenses and persist within host cells. Host-directed therapies 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 purinergic receptor 7, 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 pathogens. In infected macrophages wherein GAPDH had been knocked down, we observed an inhibition of LL-37-mediated autophagy which was rescued by GAPDH overexpression. 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 suggest a moonlighting role of GAPDH in regulating cellular phenotypic responses of LL-37 resulting in reduction of M.tb burden.

Original languageEnglish (US)
Pages (from-to)581-598
Number of pages18
JournalJournal of Innate Immunity
Volume15
Issue number1
DOIs
StatePublished - Apr 20 2023
Externally publishedYes

Keywords

  • GAPDH
  • Host-directed therapy
  • LL-37
  • Macrophage
  • Mycobacterium tuberculosis
  • Receptor
  • Trafficking

ASJC Scopus subject areas

  • Immunology and Allergy

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