Journal article
RbdB, a Rhomboid Protease Critical for SREBP Activation and Virulence in Aspergillus fumigatus
mSphere, Vol.1(2), e00035-16
03/01/2016
DOI: 10.1128/mSphere.00035-16
PMCID: PMC4863583
PMID: 27303716
Abstract
SREBP transcription factors play a critical role in fungal virulence; however, the mechanisms of sterol regulatory element binding protein (SREBP) activation in pathogenic fungi remains ill-defined. Screening of the Neurospora crassa whole-genome deletion collection for genes involved in hypoxia responses identified a gene for an uncharacterized rhomboid protease homolog, rbdB, required for growth under hypoxic conditions. Loss of rbdB in Aspergillus fumigatus also inhibited growth under hypoxic conditions. In addition, the A. fumigatus Delta rbdB strain also displayed phenotypes consistent with defective SREBP activity, including increased azole drug susceptibility, reduced siderophore production, and full loss of virulence. Expression of the basic helix-loop-helix (bHLH) DNA binding domain of the SREBP SrbA in Delta rbdB restored all of the phenotypes linking RdbB activity with SrbA function. Furthermore, the N-terminal domain of SrbA containing the bHLH DNA binding region was absent from Delta rbdB under inducing conditions, suggesting that RbdB regulates the protein levels of this important transcription factor. As SrbA controls clinically relevant aspects of fungal pathobiology in A. fumigatus, understanding the mechanisms of SrbA activation provides opportunities to target this pathway for therapeutic development.
IMPORTANCE Aspergillus fumigatus causes life-threatening infections, and treatment options remain limited. Thus, there is an urgent need to find new therapeutic targets to treat this deadly disease. Previously, we have shown that SREBP transcription factors and their regulatory components are critical for the pathobiology of A. fumigatus. Here we identify a role for RbdB, a rhomboid protease, as an essential component of SREBP activity. Our results indicate that mutants lacking rbdB have growth defects under hypoxic conditions, are hypersusceptible to voriconazole, lack extracellular siderophore production, and fail to cause disease in a murine model of invasive pulmonary aspergillosis. This study increases our understanding of the molecular mechanisms involved in SREBP activation in pathogenic fungi and provides a novel therapeutic target for future development.
Details
- Title: Subtitle
- RbdB, a Rhomboid Protease Critical for SREBP Activation and Virulence in Aspergillus fumigatus
- Creators
- Sourabh Dhingra - Dartmouth CollegeCaitlin H. Kowalski - Dartmouth CollegeArsa Thammahong - Dartmouth CollegeSarah R. Beattie - Dartmouth CollegeKatherine M. Bultman - Dartmouth CollegeRobert A. Cramer - Dartmouth College
- Resource Type
- Journal article
- Publication Details
- mSphere, Vol.1(2), e00035-16
- DOI
- 10.1128/mSphere.00035-16
- PMID
- 27303716
- PMCID
- PMC4863583
- NLM abbreviation
- mSphere
- ISSN
- 2379-5042
- eISSN
- 2379-5042
- Publisher
- Amer Soc Microbiology
- Number of pages
- 10
- Grant note
- 2R01AI081838 / National Institute of Allergy and Infectious Diseases (NIAID); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) Burroughs Wellcome Fund (BWF); Burroughs Wellcome Fund Cystic Fibrosis Foundation; Italian Cystic Fibrosis Research Foundation R01AI081838 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P30GM106394 / National Institute of General Medicine Sciences (NIGMS) P30GM106394 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 03/01/2016
- Academic Unit
- Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984353846402771
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