Protein Degradation by the Ubiquitin-Proteasome Pathway and Organ Fibrosis

H.      Fukasawa; Y.      Fujigaki; T.      Yamamoto; A.      Hishida; M.      Kitagawa

Abstract

Abnormal and exaggerated deposition of extracellular matrix proteins is the common feature of fibrotic diseases. The resulting fibrosis disrupts the normal architecture of the affected organs and finally leads to their dysfunction and failure. At present, there are no effective therapies for fibrotic diseases. Protein degradation via the ubiquitin-proteasome system is the major pathway for non-lysosomal proteolysis and controls many critical cellular functions including cell-cycle progression, deoxyribonucleic acid repair, growth and differentiation. Therefore, aberration of the system leads to dysregulation of cellular homeostasis and development of many diseases such as cancers, degenerative diseases and fibrotic diseases. Although the ubiquitin-proteasome system has mainly been investigated in the field of cancers so far and several anti-cancer drugs that modulate the activity of the system have been used clinically, the recent findings regarding the system and fibrosis can provide a rational basis for the discovery of novel therapy for fibrotic diseases. In this article, we discuss (i) the basic mechanism of the ubiquitin-proteasome system and (ii) the recent findings regarding the association between the system and pathological organ fibrosis. These examples indicate that the ubiquitin-proteasome system plays diverse roles in the progression of fibrotic diseases, and further studies of the system are expected to reveal new strategies for overcoming pathological fibrosis.

Keywords: E3 ubiquitin ligase, extracellular matrix, organ fibrosis, protein degradation, 26S proteasome, ubiquitin, fibrotic diseases, cellular homeostasis, exaggerated deposition, anti-cancer drugs