The MRNA Stability Factor Khd4 Defines a Specific MRNA Regulon for Membrane Trafficking in the Pathogen

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2023 Aug 17

PMID 37590419

Authors

Srimeenakshi Sankaranarayanan

Carl Haag

Patrick Petzsch

Karl Kohrer

Anna Matuszynska

Kathi Zarnack

Michael Feldbrugge

Affiliations

Soon will be listed here.

Abstract

Fungal pathogens depend on sophisticated gene expression programs for successful infection. A crucial component is RNA regulation mediated by RNA-binding proteins (RBPs). However, little is known about the spatiotemporal RNA control mechanisms during fungal pathogenicity. Here, we discover that the RBP Khd4 defines a distinct mRNA regulon to orchestrate membrane trafficking during pathogenic development of . By establishing hyperTRIBE for fungal RBPs, we generated a comprehensive transcriptome-wide map of Khd4 interactions in vivo. We identify a defined set of target mRNAs enriched for regulatory proteins involved, e.g., in GTPase signaling. Khd4 controls the stability of target mRNAs via its cognate regulatory element AUACCC present in their 3' untranslated regions. Studying individual examples reveals a unique link between Khd4 and vacuole maturation. Thus, we uncover a distinct role for an RNA stability factor defining a specific mRNA regulon for membrane trafficking during pathogenicity.

Citing Articles

Microbial iCLIP2: enhanced mapping of RNA-protein interaction by promoting protein and RNA stability.

Stoffel N, Sankaranarayanan S, Muentjes K, Muntjes K, Kortel N, Busch A RNA. 2024; 31(2):258-272.

PMID: 39658098 PMC: 11789484. DOI: 10.1261/rna.080193.124.

The RNA world of fungal pathogens.

Sankaranarayanan S, Kwon S, Heimel K, Feldbrugge M PLoS Pathog. 2023; 19(11):e1011762.

PMID: 38032970 PMC: 10688622. DOI: 10.1371/journal.ppat.1011762.

The mRNA stability factor Khd4 defines a specific mRNA regulon for membrane trafficking in the pathogen .

Sankaranarayanan S, Haag C, Petzsch P, Kohrer K, Matuszynska A, Zarnack K Proc Natl Acad Sci U S A. 2023; 120(34):e2301731120.

PMID: 37590419 PMC: 10450656. DOI: 10.1073/pnas.2301731120.

References

Berepiki A, Lichius A, Read N . Actin organization and dynamics in filamentous fungi. Nat Rev Microbiol. 2011; 9(12):876-87. DOI: 10.1038/nrmicro2666. View

Elson S, Noble S, Solis N, Filler S, Johnson A . An RNA transport system in Candida albicans regulates hyphal morphology and invasive growth. PLoS Genet. 2009; 5(9):e1000664. PMC: 2739428. DOI: 10.1371/journal.pgen.1000664. View

Sankaranarayanan S, Haag C, Petzsch P, Kohrer K, Matuszynska A, Zarnack K . The mRNA stability factor Khd4 defines a specific mRNA regulon for membrane trafficking in the pathogen . Proc Natl Acad Sci U S A. 2023; 120(34):e2301731120. PMC: 10450656. DOI: 10.1073/pnas.2301731120. View

Vlasova-St Louis I, Bohjanen P . Coordinate regulation of mRNA decay networks by GU-rich elements and CELF1. Curr Opin Genet Dev. 2011; 21(4):444-51. PMC: 3146975. DOI: 10.1016/j.gde.2011.03.002. View

Hargrove J, Schmidt F . The role of mRNA and protein stability in gene expression. FASEB J. 1989; 3(12):2360-70. DOI: 10.1096/fasebj.3.12.2676679. View

Diaz-Munoz M, Osma-Garcia I . The RNA regulatory programs that govern lymphocyte development and function. Wiley Interdiscip Rev RNA. 2021; 13(1):e1683. DOI: 10.1002/wrna.1683. View

Bayne R, Jayachandran U, Kasprowicz A, Bresson S, Tollervey D, Wallace E . Yeast Ssd1 is a non-enzymatic member of the RNase II family with an alternative RNA recognition site. Nucleic Acids Res. 2021; 50(5):2923-2937. PMC: 8934651. DOI: 10.1093/nar/gkab615. View

Thompson M, Ceccarelli A, Ish-Horowicz D, Davis I . Dynamically regulated transcription factors are encoded by highly unstable mRNAs in the larval brain. RNA. 2023; 29(7):1020-1032. PMC: 10275270. DOI: 10.1261/rna.079552.122. View

Rojas A, Fuentes G, Rausell A, Valencia A . The Ras protein superfamily: evolutionary tree and role of conserved amino acids. J Cell Biol. 2012; 196(2):189-201. PMC: 3265948. DOI: 10.1083/jcb.201103008. View

10.

Patino-Medina J, Valle-Maldonado M, Maldonado-Herrera G, Perez-Arques C, Jacome-Galarza I, Diaz-Perez C . Role of Arf-like proteins (Arl1 and Arl2) of Mucor circinelloides in virulence and antifungal susceptibility. Fungal Genet Biol. 2019; 129:40-51. DOI: 10.1016/j.fgb.2019.04.011. View

11.

Kumamoto C, Vinces M . Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell Microbiol. 2005; 7(11):1546-54. DOI: 10.1111/j.1462-5822.2005.00616.x. View

12.

Kolberg L, Raudvere U, Kuzmin I, Vilo J, Peterson H . gprofiler2 -- an R package for gene list functional enrichment analysis and namespace conversion toolset g:Profiler. F1000Res. 2021; 9. PMC: 7859841. DOI: 10.12688/f1000research.24956.2. View

13.

Miller J, Reese J . Ccr4-Not complex: the control freak of eukaryotic cells. Crit Rev Biochem Mol Biol. 2012; 47(4):315-33. PMC: 3376659. DOI: 10.3109/10409238.2012.667214. View

14.

Loubradou G, Brachmann A, Feldbrugge M, Kahmann R . A homologue of the transcriptional repressor Ssn6p antagonizes cAMP signalling in Ustilago maydis. Mol Microbiol. 2001; 40(3):719-30. DOI: 10.1046/j.1365-2958.2001.02424.x. View

15.

Kalem M, Subbiah H, Leipheimer J, Glazier V, Panepinto J . Puf4 Mediates Post-transcriptional Regulation of Cell Wall Biosynthesis and Caspofungin Resistance in Cryptococcus neoformans. mBio. 2021; 12(1). PMC: 7844544. DOI: 10.1128/mBio.03225-20. View

16.

Bottin A, Kamper J, Kahmann R . Isolation of a carbon source-regulated gene from Ustilago maydis. Mol Gen Genet. 1996; 253(3):342-52. DOI: 10.1007/pl00008601. View

17.

Bolker M, Kahmann R, Steinberg G . A putative endosomal t-SNARE links exo- and endocytosis in the phytopathogenic fungus Ustilago maydis. EMBO J. 2000; 19(9):1974-86. PMC: 305698. DOI: 10.1093/emboj/19.9.1974. View

18.

Just W, Peranen J . Small GTPases in peroxisome dynamics. Biochim Biophys Acta. 2016; 1863(5):1006-13. DOI: 10.1016/j.bbamcr.2016.01.004. View

19.

Kuttan A, Bass B . Mechanistic insights into editing-site specificity of ADARs. Proc Natl Acad Sci U S A. 2012; 109(48):E3295-304. PMC: 3511710. DOI: 10.1073/pnas.1212548109. View

20.

Erwig L, Gow N . Interactions of fungal pathogens with phagocytes. Nat Rev Microbiol. 2016; 14(3):163-76. DOI: 10.1038/nrmicro.2015.21. View