Ubiquitination and Proteolysis in Acute Lung Injury

Abstract

CHEST The Ubiquitin Proteasome SystemThe Discovery of the Ubiquitin Proteasome System P rotein turnover plays an important role in a broad spectrum of cellular processes. Notably, approximately 3% to 5% of our cellular proteins are degraded and resynthesized daily. 1 Until the mid-1970s it was widely believed that all intracellular proteins were degraded at the same rate in lysosomes in a nonspecifi c manner, despite the fact that proteins have a wide range of half-lives. 1 The existence of a novel, highly regulated, and specifi c degradation pathway was fi rst proposed by Ciechanover and colleagues 2 and Hershko and colleagues, 3 which was in agreement with the discovery of an ATP-dependent proteolytic system in reticulocytes that lack lysosomes. 4 As it was described 2 years later, this novel degradation pathway was mediated by a small protein of 76 amino acid residues, termed ATP-dependent proteolysis factor-1 or ubiquitin. 5 , 6 The Ubiquitin Enzymatic Cascade During ubiquitination, target proteins become "marked" as ubiquitin covalently conjugates via its C-terminal glycine to protein substrates at the ´ -amino group of their lysine residues. 7 Conjugation of ubiquitin to a target protein occurs via an enzymatic cascade. 1 , 7 Ubiquitin is fi rst activated by an ATP-dependent E1 ubiquitin-activating enzyme by the formation of a thiolester bond between the E1 enzyme and ubiquitin. Ubiquitin is then transferred via a transthiolation Ubiquitination is a posttranslational modifi cation that regulates a variety of cellular functions depending on timing, subcellular localization, and type of tagging, as well as modulators of ubiquitin binding leading to proteasomal or lysosomal degradation or nonproteolytic modifi cations. Ubiquitination plays an important role in the pathogenesis of acute lung injury (ALI) and other lung diseases with pathologies secondary to infl ammation, mechanical ventilation, and decreased physical mobility. Particularly, ubiquitination has been shown to affect alveolar epithelial barrier function and alveolar edema clearance by targeting the Na,K-ATPase and epithelial Na 1 channels upon lung injury. Notably, the proteasomal system also exhibits distinct functions in the extracellular space, which may contribute to the pathogenesis of ALI and other pulmonary diseases. Better understanding of these mechanisms may ultimately lead to novel therapeutic modalities by targeting elements of the ubiquitination pathway.CHEST 2012; 141( 3 ): 763 -771Abbreviations : ALI 5 acute lung injury ; ARDS 5 acute respiratory distress syndrome ; ELF 5 epithelial lining fl uid ; ENaC 5 epithelial Na 1 channels ; NEDD8 5 neural precursor cell expressed, developmentally downregulated 8 ; pVHL 5 von Hippel Lindau protein; RING 5 really interesting new gene

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

“…This suggests activation of cytotoxic activity from mast cells and granulocytes and activation of inflammation and apoptosis in all infected mice. Four of the proteins, ␣-2-macroglobulin, complement C3, hemopexin, and proteasome subunit, were lower in uninfected mice, and these are associated with general lung damage and inflammation common in all the infected mice (28)(29)(30)(31). Twelve proteins were significantly differentially expressed for mice infected with RS compared to the other mouse groups (Table 3).…”

“…Interestingly, 10 of the 12 were more abundant, including chitinase and iron/heme-associated proteins. For the proteins that were lower in abundance, fibronectin and inter-␣-trypsin inhibitor are both biomarkers associated with chronic obstructive pulmonary disease (COPD) and inflammatory processes when found in abundance, suggesting that RS does not induce inflammation via this mechanism (31,32). Ten significantly differentially expressed proteins were found in mice infected with Silveira compared to the other groups (Table 4).…”

Role of Linear Ubiquitination in Health and Disease

“…A variety of cancers, including colorectal tumors and pancreatic and lung carcinomas, are prone to develop with disruption of ubiquitination events (2,77). In the lung, the ubiquitin proteasome system plays a critical role in homeostasis and disease, because it is involved in the adaptation to hypoxia through the degradation of the Na, K-ATPase (78,79) and the regulation of ion balance and fluid transport in cystic fibrosis (80).…”

Protein expression profile of rat type two alveolar epithelial cells during hyperoxic stress and recovery

“…Ubiquitination and proteolysis are also thought to play critical roles in ALI (59). These processes indirectly affect epithelial barrier function and alveolar edema clearance by targeting Na,K-ATPase (29) and epithelial sodium channels (55).…”