# EPHA5 regulates antifungal innate immunity by phosphorylating EPHB2 and Dectin-1

## TL;DR

The paper shows how EPHA5 helps the immune system fight fungal infections by activating key proteins like EPHB2 and Dectin-1.

## Contribution

The study identifies EPHA5 as a novel upstream kinase that activates EPHB2 and Dectin-1 during antifungal immunity.

## Key findings

- EPHA5 phosphorylates EPHB2 and Dectin-1 to activate antifungal signaling pathways.
- Mice lacking EPHA5 show increased susceptibility to Candida albicans infection.
- The study reveals a new mechanism for immune response activation against fungal pathogens.

## Abstract

Invasive fungal infections (IFIs) have emerged as a significant health threat and cause approximately 3.75 million deaths per year globally. Understanding the detailed mechanism of the immune response to eliminate invasive fungal pathogens may help to provide new insights for the development of antifungal methods and drugs. Previously, we reported that the tyrosine kinase receptor EPH receptor B2 (EPHB2) is a coreceptor of β-glucan and phosphorylates Syk to activate the antifungal downstream signaling pathway. However, how EPHB2 is activated after fungal infection is still unknown. In this study, we show that EPHA5 plays a critical role in antifungal immunity by phosphorylating EPHB2 and Dectin-1 after fungal infection, which facilitates the recruitment and activation of Syk and subsequent activation of downstream antifungal signaling pathways. Additionally, we showed that EphA5-deficient mice exhibited increased susceptibility to Candida albicans infection, with increased fungal burdens and impaired immune cell recruitment. This study provides not only a mechanistic explanation for EPHB2 and Dectin-1 activation after fungal infection but also new insights into potential therapeutic strategies for treating IFIs.

Invasive fungal infections (IFIs) have emerged as a significant health threat, and knowledge of the immune response to eliminate invasive fungal pathogens may provide new targets and methods for the prevention or treatment of IFIs. Previously, we reported that EPHB2 is a coreceptor of β-glucan and plays a critical role in innate antifungal immunity, but the detailed mechanism by which EPHB2 is activated after fungal infection is still unknown. Here, by using cellular and mouse fungal infection models, we report that EPHA5 is an upstream kinase for EPHB2 and Dectin-1 after fungal infection, which facilitates the subsequent activation of downstream antifungal signaling pathways. This study provides not only a detailed mechanism upstream of EPHB2 and Dectin-1 but also a potential therapeutic target for IFIs.