Intracellular proteolytic systems in alcohol-induced tissue injury

Alcohol Research & Health, Winter, 2003 by Terrence M. Donohue, Jr., Natalia A. Osna

The Ubiquitin-Proteasome System and Alcohol-Induced Tissue Inflammation. Long-term alcohol consumption can cause inflammation of the liver tissue and liver cell death, leading eventually to liver injury (i.e., fibrosis and cirrhosis). The mechanisms involved in inflammation and cell death are complex, but one central cellular mechanism that underlies both these processes is the activation of a protein called nuclear factor kappa B (NF[kappa]B). NF[kappa]B belongs to a class of proteins called transcription factors, which bind to DNA near certain genes and enhance the "reading" (i.e., transcription) of those genes and, subsequently, the synthesis of the proteins encoded by those genes. NF[kappa]B enhances the transcription of several genes involved in inflammation and cell death. Because it governs such potentially detrimental genes, the activity of NF[kappa]B normally is tightly controlled. Thus, most of the time NF[kappa]B is tethered to an inhibitor protein that prevents NF[kappa]B from interacting with DNA. Under conditions of oxidative stress, however, a series of reactions occur that lead to the ubiquitylation of this inhibitor protein. As a result, the proteasome degrades the inhibitor protein, NF[kappa]B becomes free to bind to DNA, and transcription of the inflammation-promoting genes can proceed. As described previously, the oxidative stress leading to this process can result from alcohol consumption. On the other hand, oxidative stress can inhibit proteasome function, as mentioned in the previous section. Researchers do not yet know exactly how these two different effects of alcohol on the proteasome system can be explained; however, it appears that after long-term (i.e., 1 to 2 months) alcohol consumption in experimental rodents (which in humans would be equivalent to about 4 years of continuous drinking), there is sufficient proteasome activity to allow NF[kappa]B activation to proceed.

Summary. Excessive alcohol consumption can impair proteolysis mediated by the ubiquitin-proteasome system through several mechanisms. First, alcohol partially inactivates the proteasomes, presumably as a result of oxidative stress-related inactivation of the enzymes. Second, alcohol consumption may block ubiquitin-mediated protein degradation by promoting the generation of [Ub.sup. 1], although the actual role of alcohol in [Ub.sup. 1] formation is not clear. This alcohol-induced impairment of proteasome function may have profound ramifications for cell viability. For example, inhibition of proteasome activity can result in the accumulation of modified, potentially toxic proteins in cells and can cause tissue inflammation as well as premature cell death by apoptosis.

The Calpains

The third major proteolytic system affected by alcohol consists of a family of intracellular proteinases called calpains, which require calcium for their activities. Several molecular forms of the calpains exist, but the two major ones are calpain I and calpain II. The various calpains can be distinguished by the amounts of calcium required for their activities--calpain I needs less calcium for its activity than calpain II.