Prolyl isomerase Pin1 promotes extracellular matrix production in hepatic stellate cells through regulating formation of the Smad3-TAZ complex

Fibrosis development is usually followed by cell death and/or inflammation, possibly resulting in an irreversible loss of organ functions [1,2]. In the case of the liver, although the regenerative capacity of hepatocytes is very high, advanced fibrotic change damages the normal structure formed by hepatocytes, in turn leading to hepatic cirrhosis, which is observed in patients with viral hepatitis, alcoholic fatty liver, nonalcoholic steatohepatitis, and other hepatic disorders development of a therapy aimed at normalization of or protection from fibrosis would potentially revolutionize the treatment of liver cirrhosis. Excessive activation of hepatic stellate cells (HSCs) is believed to be essential for the induction and progression of liver fibrosis [3]. Normally, HSCs are in a resting state and show no activity, while HSCs are activated and acquire the ability to produce extracellular matrix (ECM) components, such as collagen and fibronectin, in response to various stimuli including liver injury [3].

Transforming growth factor β (TBFβ) is a major ligand which enhances the release of ECM components. Once TGFβ associates with its receptor on cell membranes, it causes transformation of HSCs through multiple pathways. Most notably, Smad signaling is well known to be highly engaged HSC activation [5,6]. TGFβ stimulation rapidly induces the phosphorylation of Smad2/3 and enables these molecules to form Smad complexes. Then they translocate from the cytosol to the nucleus and binds to the Smad binding element (SBE) on DNA, thereby increasing the expressions of fibrotic genes [7].

Recently, the Hippo pathway has also attracted considerable attention as a novel regulator of tissue fibrosis. The Hippo pathway, the major components of which are transcriptional co-activator Yes-associated protein (YAP) and WW domain-containing transcription regulator (WWTR: also referred to as TAZ), was originally reported to regulate the sizes of cells or organs [[8], [9], [10]]. In the nucleus, YAP and TAZ bind to transcriptional factor TEAD and promote the expressions of fibrotic and cell proliferation-related genes [10,11]. Furthermore, multiple kinases, such as Merlin, Mst1/2 and LATS1/2, phosphorylate YAP/TAZ and induce their translocation to the cytosol. Then, as a consequence, YAP/TAZ complexes are degraded by the ubiquitin-proteasome system [10]. In this way, the subcellular localization of YAP/TAZ is involved in the on-off switch of the Hippo pathway. Interestingly, they can function cooperatively with other factors, such as Smad3, and Smad3 or TEAD transcriptional activity is regulated by such associations [12].

On the other hand, prolyl isomerase Pin1 is a unique enzyme which isomerizes the proline residue in the motif containing pSer/pThr-Pro of the target proteins. Thereby, Pin1 engages in regulating the cell cycle, signal transduction and the development of several diseases [[13], [14], [15], [16]]. We previously reported that Pin1 expressions in mouse livers were dramatically increased by a methionine-choline deficient diet or a high fat diet, and that Pin1 null mice showed marked resistance to the development of hepatic lipid accumulation as well as fibrotic changes [17]. Resistance to fibrosis development in Pin1 KO mice is also reportedly observed in the kidneys and lungs [[18], [19], [20], [21]]. Thus, we speculate that Pin1 is a key player in ECM productions. In this study, we employed the LX-2 cell line, i.e., HSCs, and demonstrated that Pin1 knockdown dramatically alleviates the inductions of TGFβ-induced fibrotic genes. As its underlying molecular mechanism, Pin1 potentiated Smad3 to interact with TAZ, thereby upregulating transcriptional activity. This is the first investigation, to our knowledge, to reveal the essential role of Pin1 in the pathogenesis of fibrotic changes.

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