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
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.
