Global fungal-host interactome mapping identifies host targets of candidalysin.
Tian-Yi ZhangYao-Qi ChenJing-Cong TanJin-An ZhouWan-Ning ChenTong JiangJin-Yin ZhaXiang-Kang ZengBo-Wen LiLu-Qi WeiYun ZouLu-Yao ZhangYue-Mei HongXiu-Li WangRun-Ze ZhuWan-Xing XuJing XiQin-Qin WangLei PanJian ZhangYang LuanRui-Xin ZhuHui WangChangbin ChenNing-Ning LiuPublished in: Nature communications (2024)
Candidalysin, a cytolytic peptide toxin secreted by the human fungal pathogen Candida albicans, is critical for fungal pathogenesis. Yet, its intracellular targets have not been extensively mapped. Here, we performed a high-throughput enhanced yeast two-hybrid (HT-eY2H) screen to map the interactome of all eight Ece1 peptides with their direct human protein targets and identified a list of potential interacting proteins, some of which were shared between the peptides. CCNH, a regulatory subunit of the CDK-activating kinase (CAK) complex involved in DNA damage repair, was identified as one of the host targets of candidalysin. Mechanistic studies revealed that candidalysin triggers a significantly increased double-strand DNA breaks (DSBs), as evidenced by the formation of γ-H2AX foci and colocalization of CCNH and γ-H2AX. Importantly, candidalysin binds directly to CCNH to activate CAK to inhibit DNA damage repair pathway. Loss of CCNH alleviates DSBs formation under candidalysin treatment. Depletion of candidalysin-encoding gene fails to induce DSBs and stimulates CCNH upregulation in a murine model of oropharyngeal candidiasis. Collectively, our study reveals that a secreted fungal toxin acts to hijack the canonical DNA damage repair pathway by targeting CCNH and to promote fungal infection.
Keyphrases
- dna damage
- candida albicans
- high throughput
- endothelial cells
- cell wall
- dna repair
- oxidative stress
- escherichia coli
- biofilm formation
- genome wide
- protein kinase
- poor prognosis
- single cell
- induced pluripotent stem cells
- transcription factor
- cell cycle
- pluripotent stem cells
- amino acid
- multidrug resistant
- mouse model
- high resolution
- cell proliferation
- circulating tumor
- risk assessment
- mass spectrometry
- long non coding rna
- reactive oxygen species
- climate change