The Aspergillus fumigatus farnesyltransferase β-subunit, RamA, mediates growth, virulence, and antifungal susceptibility

Tiffany S. Norton, Qusai Al Abdallah, Amy M. Hill, Rachel V. Lovingood, Jarrod Fortwendel

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Post-translational prenylation mechanisms, including farnesylation and geranylgeranylation, mediate both subcellular localization and protein-protein interaction in eukaryotes. The prenyltransferase complex is an αβ heterodimer in which the essential α-subunit is common to both the farnesyltransferase and the geranylgeranyltransferase type-I enzymes. The β-subunit is unique to each enzyme. Farnesyltransferase activity is an important mediator of protein localization and subsequent signaling for multiple proteins, including Ras GTPases. Here, we examined the importance of protein farnesylation in the opportunistic fungal pathogen Aspergillus fumigatus through generation of a mutant lacking the farnesyltransferase β-subunit, ramA. Although farnesyltransferase activity was found to be non-essential in A. fumigatus, diminished hyphal outgrowth, delayed polarization kinetics, decreased conidial viability, and irregular distribution of nuclei during polarized growth were noted upon ramA deletion (ΔramA). Although predicted to be a target of the farnesyltransferase enzyme complex, we found that localization of the major A. fumigatus Ras GTPase protein, RasA, was only partially regulated by farnesyltransferase activity. Furthermore, the farnesyltransferase-deficient mutant exhibited attenuated virulence in a murine model of invasive aspergillosis, characterized by decreased tissue invasion and development of large, swollen hyphae in vivo. However, loss of ramA also led to a Cyp51A/B-independent increase in resistance to triazole antifungal drugs. Our findings indicate that protein farnesylation underpins multiple cellular processes in A. fumigatus, likely due to the large body of proteins affected by ramA deletion.

Original languageEnglish (US)
Pages (from-to)1401-1416
Number of pages16
JournalVirulence
Volume8
Issue number7
DOIs
StatePublished - Oct 3 2017

Fingerprint

Farnesyltranstransferase
Aspergillus fumigatus
Virulence
Prenylation
ras Proteins
Growth
Protein Prenylation
Proteins
Enzymes
Dimethylallyltranstransferase
Triazoles
Aspergillosis
Hyphae
Eukaryota
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

The Aspergillus fumigatus farnesyltransferase β-subunit, RamA, mediates growth, virulence, and antifungal susceptibility. / Norton, Tiffany S.; Al Abdallah, Qusai; Hill, Amy M.; Lovingood, Rachel V.; Fortwendel, Jarrod.

In: Virulence, Vol. 8, No. 7, 03.10.2017, p. 1401-1416.

Research output: Contribution to journalArticle

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