Abstract
BackgroundFarnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily and is a ligand-activated transcription factor essential for maintaining liver and intestinal homeostasis. FXR is protective against carcinogenesis and inflammation in liver and intestine as demonstrated by the development of inflammation and tumors in the liver and intestine of FXR knock-out mice. However, mechanisms for the protective effects of FXR are not completely understood. This study reports a novel role of FXR in regulating expression of Sqstm1, which encodes for p62 protein. p62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-κB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm1 may serve as a protective mechanism.Methods and ResultsThis study showed that FXR bound to the Sqstm1 gene in both mouse livers and ileums as determined by chromatin immunoprecipitation. In addition, FXR activation enhanced transcriptional activation of Sqstm1 in vitro. However, wild-type mice treated with GW4064, a synthetic FXR ligand, showed that FXR activation induced mRNA and protein expression of Sqstm1/p62 in ileum, but not in liver. Interestingly, FXR-transgenic mice showed induced mRNA expression of Sqstm1 in both liver and ileum compared to wild-type mice.ConclusionsOur current study has identified a novel role of FXR in regulating the expression of p62, a key factor in protein degradation and cell signaling. Regulation of p62 by FXR indicates tissue-specific and gene-dosage effects. Furthermore, FXR-mediated induction of p62 may implicate a protective mechanism of FXR.
Highlights
Our current study has identified a novel role of Farnesoid X Receptor (FXR) in regulating the expression of p62, a key factor in protein degradation and cell signaling
FXR-mediated induction of p62 may implicate a protective mechanism of FXR
Autophagy was strictly thought of as a bulk protein degradation pathway until the discovery that it performs selective degradation of polyubiquitinated proteins via sequestosome1(Sqstm1), which encodes for p62 protein. p62 is often found in cellular protein aggregates because it interacts with ubiquitinated proteins through its C-terminal ubiquitin associated (UBA) domain [1]. p62 interacts with microtubule light chain 3 (LC3), an autophagy protein, via its LC3 interacting region (LIR)
Summary
Autophagy was strictly thought of as a bulk protein degradation pathway until the discovery that it performs selective degradation of polyubiquitinated proteins via sequestosome1(Sqstm1), which encodes for p62 protein. p62 is often found in cellular protein aggregates because it interacts with ubiquitinated proteins through its C-terminal ubiquitin associated (UBA) domain [1]. p62 interacts with microtubule light chain 3 (LC3), an autophagy protein, via its LC3 interacting region (LIR). P62 is able to activate the nuclear factor kappa-light chain-enhancer of activated B cells (NF-kB) pathway [5,6,7]. P62 activates nuclear factor erythroid 2-related factor 2 (Nrf2) by binding to kelch-like ECHassociated protein 1 (Keap1), which is important for inducing expression of genes involved in the oxidative stress response [9,10,11]. This study reports a novel role of FXR in regulating expression of Sqstm, which encodes for p62 protein. P62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-kB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm may serve as a protective mechanism
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