The role of the ubiquitin proteasome pathway in keratin intermediate filament protein degradation.
Lung injury, whether caused by hypoxic or mechanical stresses, elicits a variety of responses at the cellular level. Alveolar epithelial cells respond and adapt to such injurious stimuli by reorganizing the cellular cytoskeleton, mainly accomplished through modification of the intermediate filament (IF) network. The structural and mechanical integrity in epithelial cells is maintained through this adaptive reorganization response. Keratin, the predominant IF expressed in epithelial cells, displays highly dynamic properties in response to injury, sometimes in the form of degradation of the keratin IF network. Post-translational modification, such as phosphorylation, targets keratin proteins for degradation in these circumstances. As with other structural and regulatory proteins, turnover of keratin is regulated by the ubiquitin (Ub)-proteasome pathway. The degradation process begins with activation of Ub by the Ub-activating enzyme (E1), followed by the exchange of Ub to the Ub-conjugating enzyme (E2). E2 shuttles the Ub molecule to the substrate-specific Ub ligase (E3), which then delivers the Ub to the substrate protein, thereby targeting it for degradation. In some cases of injury and IF-related disease, aggresomes form in epithelial cells. The mechanisms that regulate aggresome formation are currently unknown, although proteasome overload may play a role. Therefore, a more complete understanding of keratin degradation--causes, mechanisms, and consequences--will allow for a greater understanding of epithelial cell biology and lung pathology alike.
Northwestern University Medical School, Pulmonary and Critical Care Medicine, 240 East Huron, McGaw 328, Chicago, IL 60611, USA.
Micah R
MR
Rogel
Ariel
A
Jaitovich
Karen M
KM
Ridge
D000818:Animals; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D007633:Keratins / Q000737:chemistry / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000201:enzymology; D015398:Signal Transduction; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D007381:Intermediate Filament Proteins; D025801:Ubiquitin; D007633:Keratins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex