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Abstract 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.

Abstract Colorectal cancer (CRC) is a multistage and highly heterogeneous malignant disease that mostly occurred in aged people accompanied by microbiota alteration. Emerging evidence has uncovered the role of bacterial microbiota in the initiation and development of CRC. However, the effects of nonbacterial members inhabiting the human body, such as fungi, archaea, and viruses, have been largely ignored. The multi‐kingdom microbiota can be altered by dietary exposures and probiotic supplements. Furthermore, the efficacy of antitumor therapeutic strategies, such as radiotherapy, chemotherapy, and immunotherapy, are also closely associated with the alteration of multi‐kingdom microbiota. In this review, we describe CRC‐associated multi‐kingdom microbiota dysbiosis and the role of daily diet on CRC progression through microbiota alteration. We then discuss the impact of microbiota in different CRC therapies and highlight the advances as well as challenges in understanding how multi‐kingdom microbiome impacts the outcome of CRC.