Published January 4, 2022 - More info
Cardiac hypertrophy is a major cause of human morbidity and mortality. Although much is known about the pathways that promote hypertrophic responses, mechanisms that antagonize these pathways have not been as clearly defined. Atrogin-1, also known as muscle atrophy F-box, is an F-box protein that inhibits pathologic cardiac hypertrophy by participating in a ubiquitin ligase complex that triggers degradation of calcineurin, a factor involved in promotion of pathologic hypertrophy. Here we demonstrated that atrogin-1 also disrupted Akt-dependent pathways responsible for physiologic cardiac hypertrophy. Our results indicate that atrogin-1 does not affect the activity of Akt itself, but serves as a coactivator for members of the Forkhead family of transcription factors that function downstream of Akt. This coactivator function of atrogin-1 was dependent on its ubiquitin ligase activity and the deposition of polyubiquitin chains on lysine 63 of Foxo1 and Foxo3a. Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype. These experiments define a role for lysine 63–linked ubiquitin chains in transcriptional coactivation and demonstrate that atrogin-1 uses this mechanism to disrupt physiologic cardiac hypertrophic signaling through its effects on Forkhead transcription factors.
Hui-Hua Li, Monte S. Willis, Pamela Lockyer, Nathaniel Miller, Holly McDonough, David J. Glass, Cam Patterson
Original citation: J Clin Invest. 2007;117(11):3211–3223. https://doi.org/10.1172/JCI31757
Citation for this corrigendum: J Clin Invest. 2022;132(1):e157373. https://doi.org/10.1172/JCI157373
The authors recently became aware that the image for the HA (Foxo3a) blot in Figure 5C was a duplicate of the image presented as the anti-Myc (atrogin-1) blot in the right panel of Figure 4E. The corresponding authors have reviewed the original data and determined that the image in Figure 5C was incorrect. The corrected figure panel appears below. Additional lanes of the His (ubiquitin) blot, which were cropped from the original figure, are also displayed. The authors have stated that these errors were inadvertent and do not change the conclusions.
The authors regret the error.