TRB3 Links the E3 Ubiquitin Ligase COP1 to Lipid Metabolism

Abstract

During fasting, increased concentrations of circulating catecholamines promote the mobilization of lipid stores from adipose tissue in part by phosphorylating and inactivating acetyl-coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis. Here, we describe a parallel pathway, in which the pseudokinase Tribbles 3 (TRB3), whose abundance is increased during fasting, stimulates lipolysis by triggering the degradation of ACC in adipose tissue. TRB3 promoted ACC ubiquitination through an association with the E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1). Indeed, adipocytes deficient in TRB3 accumulated larger amounts of ACC protein than did wild-type cells. Because transgenic mice expressing TRB3 in adipose tissue are protected from diet-induced obesity due to enhanced fatty acid oxidation, these results demonstrate how phosphorylation and ubiquitination pathways converge on a key regulator of lipid metabolism to maintain energy homeostasis.

Developmental roles of tribbles protein family members

“…This down-regulation of Tribs is critical to fat cell formation as on the one hand, continuous expression of Trib3 or Trib2 effectively blocks proliferation and adipogenesis, while on the other, knockdown leads to premature MCE and differentiation (Bezy et al, 2007;Naiki et al, 2007). How Tribs regulate the cell cycle in preadipocytes is not clear, but this block to differentiation is exerted in several ways: (1) repression of the activity of key transcription factors including C/EBPb, C/ EBPa (Bezy et al, 2007) and PPARg2 (Takahashi et al, 2008), (2) inhibition of Akt phosphorylation of Foxo1, which must be inactivated to allow fat cell development to proceed, and (3) degradation of acetyl coenzyme A carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis (Qi et al, 2006). In addition, Trib1 binds LAP, the activating isoform of C/ EBPb, indicating that each Trib isoform contributes to the control of adipogenesis (Naiki et al, 2007).…”

“…In the cytoplasm, Tribs direct the proteosomal degradation of key signaling proteins, including ACC1 (Qi et al, 2006), SMURF1, FoxO (Matsumoto et al, 2006) and C/ EBP Naiki et al, 2007;Selim et al, 2007;Dedhia et al, 2010;Keeshan et al, 2010;Grandinetti et al, 2011). Also in the cytoplasm, Tribs bind to inactivate LAP (Naiki et al, 2007), MKKs (Kiss-Toth et al, 2004;Wang et al, 2011), and Akt (Du et al, 2003).…”

“…Complementarily, Trib3 binds and directs ACC to the proteosome to promote lipolysis (Qi et al, 2006). These findings have unleashed a torrent of studies focused on Trib3 as an endogenous antagonist of insulin signaling modulating glucose metabolism and fatty acid oxidation during tissue homeostasis.…”

Trb3 Regulates LR Axis Formation in Zebrafish Embryos

“…TRIBBLES3 (TRB3) was identified in neuronal cells and is also called NIPK, SKIP3, and SINK (Bowers et al, 2003;Wu et al, 2003). TRB3 modulates NF-κB signaling, lipid metabolism and insulin metabolism (Du et al, 2003;Qi et al, 2006). It also regulates cell cycle via negative modulation of Slbo and String in Drosophila (Mata et al, 2002).…”

“…It also regulates cell cycle via negative modulation of Slbo and String in Drosophila (Mata et al, 2002). TRB3 acts as an adopter/mediator molecule in the photomorphogenic protein 1 (COP1) that mediates degradation of acetyl-coenzyme A carboxylase (ACC) (Qi et al, 2006) and downregulates SMAD specific E3 ubiquitin regulatory factors 1/2 (Smurf1/2) (Chan at al., 2007;Hua et al, 2011). TRB3 is a key molecule in muscle differentiation via PKB/Akt signaling pathways (Kato and Du, 2007), a potent target of various physiological responses like hypoxia (Rzymski et al, 2008), ER stress (Avery et al, 2010), oxidative stress and nutrient deficiency in various cell types (Jousse et al, 2007).…”