Ubiquitin, a novel paracrine messenger of cardiac cell survival

Ubiquitin is a highly conserved and ubiquitously expressed protein that covalently binds other peptides by a lysine (K) residue. Traditionally, the role of ubiquitin is associated with the proteolytic function of the proteasome in what is known as the ubiquitin-proteasome system (UPS), responsible for the degradation of about 70–90% of intracellular proteins.1,2 In the UPS, ubiquitin binds the proteins to be degraded in a process known as ubiquitination and transfers them to the proteasome for proteolysis. Ubiquitination results from the formation of a peptide bond between the C-terminal carboxyl group of ubiquitin and the e-amino group of a lysine residue of the target protein, and this is followed by the synthesis of a multi-ubiquitin chain in which the e-amino group of the lysine-48 residue of the conjugated ubiquitin (UbK48) is bound to the C-terminal carboxyl group of the incoming ubiquitin moiety.3 Ubiquitination of a target protein largely depends on the identity of specific members of the large family of E3 ubiquitin ligases, which catalyze the formation of the peptide bond between ubiquitin and the client.4 Poly-ubiquitination of the client protein signals its targeting to the proteasome for degradation by several proteolytic enzymes, which is accompanied by the recycling of the ubiquitin units.5 Proper function of the UPS is critical for cellular homeostasis, and its dysfunction participates in multiple forms of disease, including in the cardiovascular system, as reviewed recently in a Spotlight issue of the Journal .6Beside this ‘canonical’ function of ubiquitin in the UPS, an emerging literature relates to ‘non-canonical’, proteasome-independent, and non-proteolytic activities of ubiquitin related to cellular functions … *Corresponding author. Tel: +1 973 972 3926; fax: +1 973 9727489, Email: deprech{at}umdnj.edu