Abstract:

All cells are equipped with a proteolytic apparatus that eliminates damaged, misfolded and incorrectly assembled proteins. The principal engine of cytoplasmic proteolysis, the 26S proteasome, requires that substrates be unfolded to gain access to the active site; consequently, it is relatively ineffective at degrading aggregated proteins. Cellular indigestion occurs when the production of aggregation-prone proteins exceeds the cell's (or organelle's) capacity to eliminate them. Cellular pathways that resolve this indigestion exist, but appear to have limited capacities. Russell bodies and aggresomes are manifestations of cellular indigestion in the endoplasmic reticulum and cytoplasmic compartments, respectively, and are often associated with disease.

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Aggresomes and Russell bodies: Symptoms of cellular indigestion?

R Kopito

R Sitia

^{Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA and}

^{Department of Molecular Pathology and Medicine, DIBIT-HSR, 20132 Milano, Italy}

^{Corresponding author. Tel: +39 02 2643 4722; Fax: +39 02 2643 4723; E-mail:}ti.rsh@aitis.r

Received 2000 May 16; Accepted 2000 Jul 25.

Abstract

All cells are equipped with a proteolytic apparatus that eliminates damaged, misfolded and incorrectly assembled proteins. The principal engine of cytoplasmic proteolysis, the 26S proteasome, requires that substrates be unfolded to gain access to the active site; consequently, it is relatively ineffective at degrading aggregated proteins. Cellular indigestion occurs when the production of aggregation-prone proteins exceeds the cell’s (or organelle’s) capacity to eliminate them. Cellular pathways that resolve this indigestion exist, but appear to have limited capacities. Russell bodies and aggresomes are manifestations of cellular indigestion in the endoplasmic reticulum and cytoplasmic compartments, respectively, and are often associated with disease.

Abstract

Acknowledgements

We thank the members of our laboratories for generating data, ideas, criticism and enthusiasm, AIRC, CNR, Ministero della Sanità, NIH-NIDDK and GM for funding our research, the chefs of the banquet at the 1999 ECBO meeting in Bologna for providing the culinary inspiration (without indigestion) for this review and Stefania Trinca for secretarial assistance. We also thank Connie Wong for her artist’s impression of protein transport across membranes (see table of contents). We apologize to the many colleagues whose excellent work we could not cite solely for limits of space.

Acknowledgements

Footnotes

Ron R. Kopito and Roberto Sitia

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