Lindberg Nutrition Articles & Resources

Breen and Espat1 have noted that the protein catabolism induced by sepsis appears to be mediated by the proteasome. Work by Qureshi et al3 has shown that Lipopolysaccharide (LPS) binds to the C2 and N3 units of the proteasome, and activates the chymotrypsin-like activity of the 2OS proteasome. Moreover, treatment with lactocystin, a proteasome-inhibitor, produced inhibition of TNF-ct secretion. These authors have further shown that treatment with lactocystin could reverse the mortality seen in galactosamine-sensitized mice treated with LPS. Further research is clearly needed, but it appears now that the proteasome may regulate virtually all of the steps in LPS signal transduction, including toll-like receptors, IRAK degradation, NF-[kappa]B activation, and phosphorylation of ERK-I, ERK-2, JNK, and p38.

The cell's response to hypoxia is mediated in part by the hypoxia-inducible transcription factor 1 (HIF-I). Zhu et al4 have summarized the mechanism for activation of HIF-I. This factor is normally controlled by the proteasome, which degrades its [alpha] subunit. In ischemia, however, the proteasome is inhibited, and the intact [alpha] subunit combines with the [beta] subunit to form HIF-I, which then activates genes controlling the response to hypoxia. Using a coronary occlusion model, Bulteau et al5 showed that proteasomes from myocardium that had been subjected to ischemia followed by reperfusion exhibited a decline in chymotrypsin-like, trypsin-like, and peptidylglutamyl-peptide hydrolase activities.

There are a number of pharmacologie agents that can inhibit proteasomes. These include lactacystin, lactacystin-[beta] lactone, peptide aldehydes (MG132, CEP1612, PSI), peptide boronates (PS341, PS273, MG262), peptide vinyl sulfones (NVLS, YVLS), and others. In a comprehensive review, Kisselev and Goldberg6 have discussed these and others and have discussed their therapeutic potentials. Proteasome inhibitors have been perhaps most studied in cancer treatment, but they clearly have a great deal of potential in other areas.

There has been a great deal of progress in the past 10 years, both in our understanding of the role of the proteasome in the regulation of cellular processes and in the development of pharmacologie agents that affect it. This cytoplasmic organelle is truly the direct opposite of the weather: nobody talks about it, but there is a great deal that we can do about it.

REFERENCES

1. Breen HB, Espat NJ. The ubiquitin-proteasome proteolysis pathway: potential target for disease intervention. JPEN. 2004;28: 272-277.

2. Qureshi N, Vogel SN, Van Way CW III, Papasian CJ, Qureshi AA, Morrison DC. The proteasome, a central regulator of inflammation and macrophage function. Immunol Res. In press.

3. Qureshi N, Perera P-Y, Splitter G, Morrison DC, Vogel SN. The proteasome as a LPS-binding protein in macrophages: toxic lipopolysaccharide activates the proteasome complex. J Immunol. 2003;171:1515-1525.

4. Zhu H, Jackson T, Bunn HF. Detecting and responding to hypoxia. Nephrol Dial Transplant. 2002;l(Suppl):3-7.

5. Bulteau AL, Lindberg KC, Humphries KM, et al. Oxidative modification and inactivation of the proteasome during coronary occlusion/reperfusion. J Biol Chem. 2001;276:30057-30063.

6. Kisselev AF, Goldberg. Proteasome inhibitors: from research tools to drug candidates. Chem Biol. 2001;8:739-758.

Charles W. Van Way, III, MD

From the Department of Surgery, University of Missouri-Kansas City, Kansas City, Missouri

Received for publication April 7, 2004.

Accepted for publication April 7, 2004.

Correspondence: Charles W. Van Way, III, MD, Department of Surgery, University of Missouri-Kansas City, 2301 Holmes Street, Kansas City, MO 64108. Electronic mail may be sent to charles. .