Journal article
A MicroRNA Processing Defect in Smokers' Macrophages Is Linked to SUMOylation of the Endonuclease DICER
The Journal of biological chemistry, Vol.289(18), pp.12823-12834
05/02/2014
DOI: 10.1074/jbc.M114.565473
PMCID: PMC4007470
PMID: 24668803
Abstract
Background:
Smoking causes a global down-regulation in alveolar macrophage miRNA expression.
Results:
Cigarette smoke exposure modifies the RNA endonuclease DICER, resulting in a microRNA processing defect.
Conclusion:
Cigarette smoke alters alveolar macrophage microRNA expression, in part, by SUMOylation of DICER.
Significance:
This is the first description of an environmental exposure causing changes in microRNA expression via post-translational modification of DICER.
Despite the fact that alveolar macrophages play an important role in smoking-related disease, little is known about what regulates their pathophysiologic phenotype. Evaluating smoker macrophages, we found significant down-regulation of multiple microRNAs (miRNAs). This work investigates the hypothesis that cigarette smoke alters mature miRNA expression in lung macrophages by inhibiting processing of primary miRNA transcripts. Studies on smoker alveolar macrophages showed a defect in miRNA maturation. Studies on the miRNA biogenesis machinery led us to focus on the cytosolic RNA endonuclease, DICER. DICER cleaves the stem-loop structure from pre-miRNAs, allowing them to dissociate into their mature 20–22-nucleotide single-stranded form. DICER activity assays confirmed impaired DICER activity following cigarette smoke exposure. Further protein studies demonstrated a decreased expression of the native 217-kDa form of DICER and an accumulation of high molecular weight forms with cigarette smoke exposure. This molecular mass shift was shown to contain SUMO moieties and could be blocked by silencing RNA directed at the primary SUMOylating ligase, Ubc9. In determining the cigarette smoke components responsible for changes in DICER, we found that
N
-acetylcysteine, an antioxidant and anti-aldehyde, protected DICER protein and activity from cigarette smoke extract. This massive down-regulation of miRNAs (driven in part by alterations in DICER) may be an important regulator of the disease-promoting macrophage phenotype found in the lungs of smokers.
Details
- Title: Subtitle
- A MicroRNA Processing Defect in Smokers' Macrophages Is Linked to SUMOylation of the Endonuclease DICER
- Creators
- Thomas J Gross - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Linda S Powers - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Ryan L Boudreau - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Brandi Brink - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Anna Reisetter - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Khushboo Goel - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Alicia K Gerke - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Ihab H Hassan - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Martha M Monick - From the Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.289(18), pp.12823-12834
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- DOI
- 10.1074/jbc.M114.565473
- PMID
- 24668803
- PMCID
- PMC4007470
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Grant note
- R01 HL079901; RO1 HL096625; R21 HL109589; P30 ES005605; UL1RR024979 / National Institutes of Health
- Alternative title
- Alterations in DICER and miRNA Levels with Cigarette Smoke
- Language
- English
- Date published
- 05/02/2014
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065382502771
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