Back to your heart: ubiquitin proteasome system-regulated signal transduction

Abstract

Awareness of the regulation of cell signaling by post-translational ubiquitination has emerged over the past 2 decades. Like phosphorylation, post-translational modification of proteins with ubiquitin can result in the regulation of numerous cellular functions, for example, the DNA damage response, apoptosis, cell growth, and the innate immune response. In this review, we discuss recently published mechanisms by which the ubiquitin proteasome system regulates key signal transduction pathways in the heart, including MAPK JNK, calcineurin, FOXO, p53, and estrogen receptors α and β. We then explore how ubiquitin proteasome system-specific regulation of these signal transduction pathways plays a role in the pathophysiology of common cardiac diseases, such as cardiac hypertrophy, heart failure, ischemia reperfusion injury, and diabetes. This article is part of a Special Section entitled "Post-translational Modification."

Figure 1. Regulation of JNK signaling by the ubiquitin ligases MuRF1 and aAtrogin-1/MAFbx

A. MuRF1 inhibits JNK signaling by preferentially binding phosphorylated c-Jun, poly-ubiquitinating it and targeting it for degradation by the proteasome in cardiac ischemia reperfusion injury (Summarized from data by Li, et al., 2011 [25]). Increasing cardiomyocyte MuRF1 has recently been shown to be cardioprotective in I/R injury both in vitro and in vivo, in part, by this mechanism, which inhibits JNK-induced apoptosis. B. Atrogin-1/MAFbx enhances JNK signaling by binding and ubiquitinating the JNK inhibitory phosphatase MKP-1 and targeting it for degradation by the proteasome (Summarized from data by Xie, et al., 2009 [26]). Increasing Atrogin-1/MAFbx in culture enhances cardiomyocyte susceptibility to I/R injury-induced apoptosis, while inhibiting Atrogin-1/MAFbx inhibits I/R-induced apoptosis experimentally in vitro.

Figure 2. Overview of FoxO signaling

Activation of transmembrane receptors by various stimuli leads to activation of AKT. ATK phosphorylates numerous targets, including FoxO transcription factors. AKT-phosphorylated FoxO is inactivated and shuttled to the cytoplasm via association with 14-3-3 proteins. In the absence of AKT activity, FoxO transcription factors transcribe ubiquitin ligases, antioxidants, and proapoptotic genes.

Figure 3. Regulation of FoxO transcription factors by the UPS

A. Multiple ubiquitin ligases can polyubiquitinate and degrade FoxO. However, FoxO activity can be augmented through B. monoubiquitination or C. noncanonical (K63 linked) ubiquitination to regulate its activity as described in the text.

Figure 4. Reported ubiquitin ligases that act upon p53 and the multiple lysines ubiquitinated that regulate steady state protein levels and/or p53 activity

Adapted from Brooks and Gu, 2011 [38]. ?=potential sites that may be ubiquitinated (not reported).