+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Damage resistance protein (Dap) contributes to azole resistance in a sterol-regulatory-element-binding protein SrbA-dependent way



Damage resistance protein (Dap) contributes to azole resistance in a sterol-regulatory-element-binding protein SrbA-dependent way



Applied Microbiology and Biotechnology 101(9): 3729-3741



The targeting of stress-response regulators has emerged as a powerful strategy to enhance azole drug efficacy and to abrogate azole drug resistance. Previously, we reported that a damage resistance protein (Dap) family, composed of DapA, DapB, and DapC, could respond to azole stress stimuli in Aspergillus fumigatus, although the exact response mechanisms remain unknown. In this study, RNA-seq analysis found that a total of 180 genes are induced by azole in a dapA-dependent manner. These genes are involved in oxidation-reduction, metabolic processes, and transmembrane transport. Following azole stress stimuli, DapA and DapC consistently show a stable endoplasmic reticulum (ER)-localization pattern. In comparison, the sterol-regulatory element-binding protein SrbA is capable of nuclear translocation from the ER after azole-stress stimuli, suggesting that SrbA, but not Daps, can directly sense azole stress. Moreover, we found that SrbA is required for the normal expression of DapA and DapC but not of DapB. In addition, in the absence of SrbA, the enhanced expression of DapA induced by azole-itraconazole is blocked, indicating that SrbA is required for the DapA response to azole stress. Double mutants together with overexpression experiments suggest that DapA might act downstream of SrbA to respond to azole stress stimuli. Compared with the ΔsrbA strain, no additional increase in sensitivity was observed in the double mutants ΔsrbAΔdapB and ΔsrbAΔdapC, indicating that DapA might be of central importance in the response to azole drugs. Thus, our findings demonstrate that Dap proteins indirectly sense azole stress and link the function of the azole stress-regulator SrbA with the role of Daps in azole susceptibility.

(PDF emailed within 0-6 h: $19.90)

Accession: 059575600

Download citation: RISBibTeXText

PMID: 28050634

DOI: 10.1007/s00253-016-8072-9


Related references

A sterol-regulatory element binding protein is required for cell polarity, hypoxia adaptation, azole drug resistance, and virulence in Aspergillus fumigatus. Plos Pathogens 4(11): E1000200-E1000200, 2008

Androgens stimulate lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element-binding protein cleavage activating protein/sterol regulatory element-binding protein pathway. Molecular Endocrinology 15(10): 1817-1828, 2001

Sterol regulatory element-binding protein (SREBP)-1: gene regulatory target for insulin resistance?. Expert Opinion on Therapeutic Targets 8(2): 141-149, 2004

Yin yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element. Endocrinology 142(1): 49-58, 2001

Metformin attenuates palmitic acid-induced insulin resistance in L6 cells through the AMP-activated protein kinase/sterol regulatory element-binding protein-1c pathway. International Journal of Molecular Medicine 35(6): 1734-1740, 2016

Intestinal insulin resistance and aberrant production of apolipoprotein B48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine. Diabetes 55(5): 1316-1326, 2006

Chronic Hyperinsulinemia Causes Selective Insulin Resistance and Down-regulates Uncoupling Protein 3 (UCP3) through the Activation of Sterol Regulatory Element-binding Protein (SREBP)-1 Transcription Factor in the Mouse Heart. Journal of Biological Chemistry 290(52): 30947-30961, 2016

Role of atypical protein kinase C in activation of sterol regulatory element binding protein-1c and nuclear factor kappa B (NFkappaB) in liver of rodents used as a model of diabetes, and relationships to hyperlipidaemia and insulin resistance. Diabetologia 52(6): 1197-1207, 2009

Association of rs8066560 variant in the sterol regulatory element-binding protein 1 (SREBP-1) and miR-33b genes with hyperglycemia and insulin resistance. Journal of Pediatric Endocrinology & Metabolism 27(7-8): 611-615, 2015

Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia. Atherosclerosis 164(1): 15-26, 2002

Sterol-dependent transcriptional regulation of sterol regulatory element-binding protein-2. Journal of Biological Chemistry 271(43): 26461-4, 1996

Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes. Diabetes 53(3): 842-846, 2004

Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. Journal of Biological Chemistry 277(22): 19353-7, 2002

Light-dependent and circadian clock-regulated activation of sterol regulatory element-binding protein, X-box-binding protein 1, and heat shock factor pathways. Proceedings of the National Academy of Sciences of the United States of America 108(12): 4864-4869, 2011

Effects of transcription factor sterol regulatory element binding protein-1c in palmitate acid-induced L6 cells insulin resistance and its mechanism. Zhonghua Yi Xue Za Zhi 95(8): 611-615, 2015