The role of K63-linked polyubiquitination in cardiac hypertrophy

Abstract

Ubiquitination, also known as ubiquitylation, is a vital post-translational modification of proteins that play a crucial role in the multiple biological processes including cell growth, proliferation and apoptosis. K63-linked ubiquitination is one of the vital post-translational modifications of proteins that are involved in the activation of protein kinases and protein trafficking during cell survival and proliferation. It also contributes to the development of various disorders including cancer, neurodegeneration and cardiac hypertrophy. In this review, we summarize the role of K63-linked ubiquitination signalling in protein kinase activation and its implications in cardiac hypertrophy. We have also provided our perspectives on therapeutically targeting K63-linked ubiquitination in downstream effector molecules of growth factor receptors for the treatment of cardiac hypertrophy.

Keywords: AKT; NF-κB; TRAF6; cardiac hypertrophy; phosphorylation; protein kinase; tumorigenesis; ubiquitination.

Figure 1

Ubiquitin and Ubiquitin modifications. A, Ubiquitin is a protein with 76 aa residues, which is highly conserved across species. It possesses 7 internal lysine residues (K6, K11, K27, K29, K33, K48 and K63) in the ubiquitin, which have been identified to be utilized for the formation of ubiquitination chains. B, The schematic representation of the ubiquitination cascade. The ubiquitin is covalently coupled with ubiquitin‐activating (E1) and then transferred to ubiquitin‐conjugating enzyme (E2), Finally, the ubiquitin ligase (E3) specifically catalyses the ubiquitination of target protein. And DUBs specifically remove ubiquitin chains from their protein substrates. C, The schematic representation of the different types of ubiquitin chains and ubiquitin signals. The question mark indicates that the roles of ubiquitin chains are largely unclear

Figure 2

A schematic diagram of the molecular mechanisms underlying K63‐linked polyubiquitination and cardiac hypertrophy. In TNF‐α pathway, TNFR recruits its adaptor protein TRADD in response to binding of TNF‐α. TRADD further recruits TRAF2, TRAF5 and RIP1 to the receptor complex. TRAF2/5‐mediated K63 polyubiquitination of RIP1 further recruits TAB2 and TAK1 in the cytoplasm, which activates TAK1 by phosphorylation. The activated RIP1‐TAK1‐TAB2 complex subsequently promotes activation of MEKKs, which in turn activates the MAP kinase kinases, culminating in MAPK activation (JNK, ERK and p38), and activates p38 and JNK. These terminal kinases then proceed to phosphorylate transcription factors within the nucleus, as well as other regulatory proteins in the nucleus. And also K63 polyubiquitination chains of NEMO increases the activity of IKK complex which leads to IκBα‐dependent activation of NF‐κB pathway. The TNF‐α pathway is regulated by deubiquitinases A20 and CYLD

Figure 3

Ubiquitination regulates activation of AKT kinase. The growth factor IGF‐1 triggers K63‐linked ubiquitination of AKT and it promotes recruitment of AKT to membrane, which subsequently phosphorylated by PDK1 and mTOR. The activated AKT translocates to the nucleus and catalyses the transcription of genes associated with the heart growth and hypertrophy. E3 ligase TRAF6 contributes to Akt kinase activation by promoting K63‐linked polyubiquitination