Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors

Megan Sheridan; Nityananda Chowdhury; Bridgette Wellslager; Natalia Oleinik; Mohamed Faisal Kassir; Han G. Lee; Mindy Engevik; Yuri Peterson; Subramanya Pandruvada; Zdzislaw M. Szulc; Özlem Yilmaz; Besim Ogretmen

iScience (Jun 2024)

Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors

Megan Sheridan,
Nityananda Chowdhury,
Bridgette Wellslager,
Natalia Oleinik,
Mohamed Faisal Kassir,
Han G. Lee,
Mindy Engevik,
Yuri Peterson,
Subramanya Pandruvada,
Zdzislaw M. Szulc,
Özlem Yilmaz,
Besim Ogretmen

Affiliations

Megan Sheridan: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Nityananda Chowdhury: Department of Oral Health Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Bridgette Wellslager: Department of Oral Health Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Natalia Oleinik: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Mohamed Faisal Kassir: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Han G. Lee: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Mindy Engevik: Department of Regenerative Medicine, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Yuri Peterson: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Subramanya Pandruvada: Department of Oral Health Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Zdzislaw M. Szulc: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
Özlem Yilmaz: Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Oral Health Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Corresponding author
Besim Ogretmen: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Corresponding author

Journal volume & issue: Vol. 27, no. 6
p. 109860

Abstract

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Summary: Mechanisms by which Porphyromonas gingivalis (P. gingivalis) infection enhances oral tumor growth or resistance to cell death remain elusive. Here, we determined that P. gingivalis infection mediates therapeutic resistance via inhibiting lethal mitophagy in cancer cells and tumors. Mechanistically, P. gingivalis targets the LC3B-ceramide complex by associating with LC3B via bacterial major fimbriae (FimA) protein, preventing ceramide-dependent mitophagy in response to various therapeutic agents. Moreover, ceramide-mediated mitophagy is induced by Annexin A2 (ANXA2)-ceramide association involving the E142 residue of ANXA2. Inhibition of ANXA2-ceramide-LC3B complex formation by wild-type P. gingivalis prevented ceramide-dependent mitophagy. Moreover, a FimA-deletion mutant P. gingivalis variant had no inhibitory effects on ceramide-dependent mitophagy. Further, 16S rRNA sequencing of oral tumors indicated that P. gingivalis infection altered the microbiome of the tumor macroenvironment in response to ceramide analog treatment in mice. Thus, these data provide a mechanism describing the pro-survival roles of P. gingivalis in oral tumors.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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