The fungal-specific subunit i/j of F1FO-ATP synthase stimulates the pathogenicity of Candida albicans independent of oxidative phosphorylation

Abstract

Invasive fungal infections are a major cause of human mortality due in part to a very limited antifungal drug arsenal. The identification of fungal-specific pathogenic mechanisms is considered a crucial step to current antifungal drug development and represents a significant goal to increase the efficacy and reduce host toxicity. Although the overall architecture of F1FO-ATP synthase is largely conserved in both fungi and mammals, the subunit i/j (Su i/j, Atp18) and subunit k (Su k, Atp19) are proteins not found in mammals and specific to fungi. Here, the role of Su i/j and Su k in Candida albicans was characterized by an in vivo assessment of the virulence and in vitro growth and mitochondrial function. Strikingly, the atp18Δ/Δ mutant showed significantly reduced pathogenicity in systemic murine model. However, this substantial defect in infectivity exists without associated defects in mitochondrial oxidative phosphorylation or proliferation in vitro. Analysis of virulence-related traits reveals normal in both mutants, but shows cell wall defects in composition and architecture in the case of atp18Δ/Δ. We also find that the atp18Δ/Δ mutant is more susceptible to attack by macrophages than wild type, which may correlate well with the abnormal cell wall function and increased sensitivity to oxidative stress. In contrast, no significant changes were observed in any of these studies for the atp19Δ/Δ. These results demonstrate that the fungal-specific Su i/j, but not Su k of F1FO-ATP synthase may play a critical role in C. albicans infectivity and represent another opportunity for new therapeutic target investigation. Lay Abstract This study aims to investigate biological functions of fungal-specific subunit i/j and subunit k of ATP synthase in C. albicans oxidative phosphorylation and virulence potential. Our results revealed that subunit i/j, and not subunit k, is critical for C. albicans pathogenicity.

Influence of the Manufacturing Method on the Adhesion of Candida albicans and Streptococcus mutans to Oral Splint Resins

“…The role of species-specific characteristics, such as the cell surface protein antigen SpaP of S. mutans [ 63 , 64 ] or the adhesion protein Hyphal wall protein 1 of C. albicans [ 65 , 66 ], remains to be clarified in the context of the initial attachment to dental resins. Differences in the ATP metabolism of fungi and bacteria might additionally explain the differential results for the two microorganisms in the performed ATP-based luminescence assay of the present study [ 67 , 68 , 69 ].…”

CpSmt3, an ortholog of small ubiquitin-like modifier, is essential for growth, organelle function, virulence, and antiviral defense in Cryphonectria parasitica

“…These downregulated proteins were implicated in a wide range of biological processes, including translation, ribosome biogenesis, the cell cycle, oxidative phosphorylation and TCA cycle, protein processing in endoplasmic reticulum, and exosome ( Supplementary Tables 4 , 5 ). Abnormalities of these cellular processes jeopardize cell growth and functions, from energy metabolism to pathogenicity ( Fernández-Álvarez et al, 2013 ; Koh and Sarin, 2018 ; Richardson, 2019 ; Zhao et al, 2021 ; Yuan et al, 2023 ). Of the SUMOylated proteins, CpSep1, CpSlt2, CpMK2, CpMK1, and Cdc48 have been shown to be virulence factors in C. parasitica ( Park et al, 2004 ; Choi et al, 2005 ; Ko et al, 2016 ; So et al, 2017 ; Jo et al, 2019 ).…”