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Review
. 2020 Jul 8;21(14):4842.
doi: 10.3390/ijms21144842.

The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome

Tiao Li  1 , Chunbin Zou  1
Affiliations
Review

The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome

Tiao Li et al. Int J Mol Sci. .

Abstract

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ARDS occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. The prevalence of ARDS is approximately 10% in patients of intensive care. There is no effective remedy with mortality high at 30-40%. Most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. Protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (DUBs). Deubiquitination plays an important role in the pathobiology of ALI/ARDS as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. In this review, we provide an overview of how DUBs emerge in pathogen-induced pulmonary inflammation and related aspects in ALI/ARDS. Better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways.

Keywords: acute lung injury/acute respiratory distress syndrome; deubiquitinating enzyme; infection; inflammation; protein stability.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Protein ubiquitin proteasomal degradation and deubiquitination. A protein destined for degradation unleashes a cascade of enzymatic activity involving ubiquitination and proteasomal degradation. E1 Ub-activating enzymes activate ubiquitin and pass the ubiquitin to E2-Ub-conjugating enzymes. E3 Ub-ligases recognize the protein substrates and couple E2-Ub-conjugating enzymes to covalently add the ubiquitin or ubiquitin moieties to the protein substrates. The ubiquitinated proteins are then degraded by the proteasome. Deubiquitinating enzymes remove the mono-ubiquitin or polyubiquitin chains from the ubiquitinated protein to stabilize the protein from proteasomal degradation and recycle ubiquitin units. Ub: ubiquitin; E1: E1 Ub-activating enzyme; E2: E2-Ub-conjugating enzyme, E3: E3 Ub-ligases; DUB: deubiquitinating enzyme.
Figure 2
Figure 2
Deubiquitination and DUBs are involved in the pathogenesis of ALI/ARDS. DUBs conduct deubiquitination that is exclusively involved in every aspects of the pathogenesis of ALI/ARDS. Microbial pathogens regulate the activity and availability of DUBs to impact host immune defense and the inflammatory response, which includes chemokine and cytokine release, macrophage activation, and neutrophil and lymphocyte infiltration. On the other hand, DUBs participate in pathogen-mediated lung epithelial and endothelial cell proliferation and death. Furthermore, DUBs may affect epithelial mucosal clearance and regulate the bacterial load in small airway alveolar epithelial cells. In addition, DUBs impair cell junctions and the air–blood barrier. AT1: alveolar type 1 epithelial cell; AT2: alvelolar type 2 epithelial cell; TGF-β: transforming growth factor-β; DUB: Deubiquinating enzyme.
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