Pathogen entry and intracellular survival within host cells critically require breaching host membranes. Here, we identify the conserved fungal protein HscA as a cross-kingdom effector in human and plant pathogens. This function depends on a single tyrosine residue in the C-terminal domain. This residue is predicted to stabilize a conformation that contributes to phagosomal damage. The human host protein p11, a negative regulator of the degradative phagosome function, is anchored by HscA to phagosomes, thereby facilitating engagement of the ESCRT- and annexin-mediated repair machinery. Functional analyses combined with phylogenetic reconstruction reveal that, although HscA is broadly conserved across fungi, effector activity evolved independently in multiple pathogenic lineages. We demonstrate this activity in the human pathogens Aspergillus fumigatus, Candida albicans, and Candida glabrata, as well as the plant pathogen Ustilago maydis. These findings suggest the convergent evolution of pathogenic HscA variants driven by similar host-derived selective pressures. They reveal a shared molecular strategy underlying fungal pathogenicity and identify HscA as a potential target for broad-spectrum antifungal interventions.
2026-11-12
Tyrosine-containing fungal HscA orthologues contribute to host membrane damage
Lei-Jie Jia¹#, Freddy A. Bernal² , Jeany Söhnlein³ ⁴, Shivam Chaudhary⁵, Johannes Sonnberger⁶, Isabel Heineking¹ ⁴, Muhammad Rafiq¹ , Zoltán Cseresnyés⁷, Franziska Kage¹ ⁴, Franziska Schmidt³, Rasha Zaher³ ⁴, Dominik Schmidt¹, Peter Hortschansky³, Xue-Min Gong⁸, Marc Thilo Figge⁴ ⁷ ⁹, Bernhard Hube⁴ ⁶ ⁹, Jan Schirawski⁵, Axel A. Brakhage³ ⁴ ⁹#
<p>1 Junior Research Group Phagosome Biology and Engineering, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI); Jena, 07745, Germany. <br>2Transfer Group Anti-infectives, Leibniz-HKI; Jena, 07745, Germany. <br>3Department of Molecular and Applied Microbiology, Leibniz-HKI; Jena, 07745, Germany. <br>4 Institute of Microbiology, Friedrich Schiller University (FSU); Jena, 07745, Germany. 5Department of Genetics, Matthias Schleiden Institute, FSU; Jena, 07743, Germany. 6Department of Microbial Pathogenicity Mechanisms, Leibniz-HKI; Jena, 07745, Germany. <br>7Department of Applied Systems Biology, Leibniz-HKI; Jena, 07745, Germany. <br>8Leibniz Institute on Aging – Fritz Lipmann Institute; Jena, 07745, Germany. </p><p>9Cluster of Excellence Balance of the Microverse, FSU; Jena, Germany. </p><p>#Corresponding author: <a href="mailto:leijie.jia@leibniz-hki.de" rel="noopener noreferrer nofollow" data-link-auto="">leijie.jia@leibniz-hki.de</a>; <a href="mailto:axel.brakhage@leibniz-hki.de" rel="noopener noreferrer nofollow" data-link-auto="">axel.brakhage@leibniz-hki.de</a></p>
Nature Communications