The orphan receptor TR3 participates in angiotensin II-induced cardiac hypertrophy by controlling mTOR signalling.
Bottom Line: TR3 was shown to form a trimer with the TSC1/TSC2 complex that specifically promoted TSC2 degradation via a proteasome/ubiquitination pathway.As a result, mTORC1, but not mTORC2, was activated; this was accompanied by increased protein synthesis, enhanced production of reactive oxygen species and enlarged cell size, thereby resulting in cardiac hypertrophy.The elimination or reduction of TR3 may reduce cardiac hypertrophy; therefore, TR3 is a potential target for clinical therapy.
Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.Show MeSH
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Mentions: Unexpectedly, we found that the endogenous and exogenous expression of TSC2 but not TSC1 decreased when TR3 was introduced into various cell types (Fig 4D and Supporting Information Fig S5A). TR3-KO mice consistently expressed TSC2 at much higher levels than WT mice (Fig 5A, top); this was also observed when comparing TR3−/− MEFs with TR3+/+ MEFs (Fig 5A, bottom). This decrease of TSC2 by AngII was attenuated in TR3−/− MEFs and TR3-KD NRCMs (Fig 5B). Similarly, CHX significantly decreased TSC2 expression in TR3+/+ MEFs but not in TR3−/− MEFs (Supporting Information Fig S5B), which indicates that TSC2 is more stable in TR3−/− MEFs than in TR3+/+ MEFs. These results strongly suggest a possible role for TR3 in the degradation of TSC2.
Affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.