Priming the Proteasome to Protect against Proteotoxicity

Abstract

Increased proteotoxic stress (IPTS) resulting from the increased production or decreased removal of abnormally folded proteins is recognized as an important pathogenic factor for a large group of highly disabling and life-threatening human diseases, such as neurodegenerative disorders and many heart diseases. The proteasome is pivotal to the timely removal of abnormal proteins but its functional capacity often becomes inadequate in the disease conditions; consequently, proteasome functional insufficiency in return exacerbates IPTS. Recent research in proteasome biology reveals that the proteasome can be activated by endogenous protein kinases, making it possible to pharmacologically prime the proteasome for treating diseases with IPTS.

Keywords: cAMP-dependent protein kinase; cGMP-dependent protein kinase; desmin-related cardiomyopathy; phosphodiesterases; proteasome; proteotoxicity.