Role of the Non-Canonical RNAi Pathway in the Antifungal Resistance and Virulence of Mucorales

• Main Authors: José Tomás Cánovas-Márquez, María Isabel Navarro-Mendoza, Carlos Pérez-Arques, Carlos Lax, Ghizlane Tahiri, José Antonio Pérez-Ruiz, Damaris Lorenzo-Gutiérrez, Silvia Calo, Sergio López-García, Eusebio Navarro, Francisco Esteban Nicolás, Victoriano Garre, Laura Murcia
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Genes
• Subjects: virulence; antifungal resistance; non-canonical RNAi; epimutant; R3B2; RdRP
• Online Access: https://www.mdpi.com/2073-4425/12/4/586

Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community claims to find targets for the development of new treatments. Here, we reviewed different studies describing the role and machinery of a novel non-canonical RNAi pathway (NCRIP) only conserved in Mucorales. Its non-canonical features are the independence of Dicer and Argonaute proteins. Conversely, NCRIP relies on RNA-dependent RNA Polymerases (RdRP) and an atypical ribonuclease III (RNase III). NCRIP regulates the expression of mRNAs by degrading them in a specific manner. Its mechanism binds dsRNA but only cuts ssRNA. NCRIP exhibits a diversity of functional roles. It represses the epimutational pathway and the lack of NCRIP increases the generation of drug resistant strains. NCRIP also regulates the control of retrotransposons expression, playing an essential role in genome stability. Finally, NCRIP regulates the response during phagocytosis, affecting the multifactorial process of virulence. These critical NCRIP roles in virulence and antifungal drug resistance, along with its exclusive presence in Mucorales, mark this pathway as a promising target to fight against mucormycosis.