What is the functional significance of VPS retromer

What is the functional significance of VPS35/retromer-turning off PTH1R signaling? The increased and sustained PTH(1–34) signaling in Vps35-deficient OB-lineage Oligomycin A corroborates well with the impaired PTH(1–34)-driven catabolic response (e.g., RANKL/OPG-expression and OC genesis). Suppression of PPP1R14C expression diminished not only the sustained endosomal PTH(1–34) signaling, but also the impaired catabolic response due to VPS35-deficiency (Figs. 9-10). These observations lead to the speculation that VPS35/retromer turning off the endosomal PTH(1–34) signaling may be critical for PTH(1–34)-induced catabolic response and bone remodeling, thus preventing a large bone-gain response. It is noteworthy that our results for PTH(1–34) responses in Vps35-deficient cells/mice are remarkably similar to that described for β-arrestin-biased ligand (D-Trp12,Tyr34)-PTH(7–34)\'s effect, which stimulates PTH1R-mediated endosomal/non-canonical β-arrestin signaling, promotes anabolic bone formation, but suppresses catabolic bone resorption (Gesty-Palmer et al., 2009; Whalen et al., 2011). It is also of interest to note that β-arrestins prolong rather than attenuate cAMP signaling triggered by GPCRs, including PTH1R and vasopressin receptor (van der Lee et al., 2013; Vilardaga et al., 2012; Whalen et al., 2011). Such β-arrestin mediated signaling is believed to be a non-canonical or endosomal signaling, as it is different from that of canonical or cell surface model. In the cell surface model, β-arrestin is thought to desensitize GPCR signaling at the plasma membrane by physically interacting with activated GPCR, such as rhodopsin and the β2-AR (Whalen et al., 2011). Another intriguing observation is that the structures of β-arrestins and the Vps26 subunit of retromer have a striking resemblance (Collins et al., 2008). Although the functional significance of this similarity remains unknown, it is possible that via VPS26, VPS35/retromer may complete with β-arrestin2 in binding to PTH1R in endosomes, thus, suppresses β-arrestin mediated non-canonical signaling. While this alternative hypothesis is of interest, it requires additional investigations. The following are the supplementary data related to this article.
Author Contributions W.–C.X. and L.X. designed research; L.X. performed experiments in Figs. 1-10; W.-F.X. established primary BMSCs cultures; L.X. and F.-L.T. contributed reagents/plasmids; J.-X.P. assisted in cell culture; W.–C.X., L.X. and L.M. analyzed data; W.–C.X. and L.X. wrote the paper.
Conflict of Interest Statement
Acknowledgments
This work was supported in part by grants from National Institutes of Health (to WCX and LM) and VA (BX000838 to WCX).
Introduction Nutrient excess and adiposity leads to chronic low-grade inflammation, which is referred to as obesity-related inflammation (Xu et al., 2003b). Obesity-related inflammation acts as a key pathogenic link between obesity and obesity-associated metabolic disorders, including insulin resistance (Xu et al., 2003a), type 2 diabetes (Duncan et al., 2003) and cancer (Howe et al., 2013). Thus, resolving the inflammation is one potential strategy to treat metabolic syndromes. Thus far, several drugs, such as metformin (Dinarello, 2010) and thiazolidinedione have been proven to restrain low-grade inflammation and therefore to treat insulin-resistance and correlated physiological functional disorders. However, further efforts are needed to develop newer and safer therapeutics to ameliorate obesity-related inflammation and reverse metabolic disorders. PPARγ, which belongs to the PPAR family of ligand-inducible transcription factors, has been well documented to play a central role in adipogenesis and low-grade inflammation. PPARγ is implicated in the regulation of immunological events, playing an important role in mediating the differentiation and activation of immune cells, as well as modifying cytokine expression patterns and cell fates, thereby remodeling the immune balance (Cipolletta et al., 2012). In particular, PPARγ has been recognized as a pivotal anti-inflammatory regulator in atherosclerosis primarily through regulating the differentiation and functional polarization of macrophages (Bouhlel et al., 2007). Macrophages are heterogeneous and plastic, and there are at least two major macrophage populations: those in a predominantly M1-polarised pro-inflammatory state and those in a predominantly M2-polarised anti-inflammatory state (Chinetti-Gbaguidi and Staels, 2011). M1 cells are efficient producers of effector molecules (ROS and NO) and inflammatory cytokines (IL-1R, TNF, IL-6, etc.) and express typical phenotypic molecules, such as CD80 and CCR7. In contrast, the various forms of M2 cells share a distinct major signature with low IL-12, low IL-23, and high IL-10 and generally have high levels of scavenger, mannose, and galactose-type receptors, and arginine metabolism within these cells is shifted to production of ornithine and polyamines via arginase. M2 cells have been shown to express high levels of certain genes, such as chitinase-like Ym1, found in inflammatory zone (FIZZ)1 (Fizz1), arginase (Arg1) and mannose receptor C type 1 (CD206); these have become classical markers of M2 cells. M1 and M2 cells have distinct chemokine and chemokine receptor repertoires and therefore orchestrate different immune responses (Mantovani et al., 2004). Manipulation of M1/M2 homeostasis has been shown to be an effective strategy for clinical treatment of some inflammatory diseases. PPARγ activation can skew macrophages towards an anti-inflammatory M2 phenotype, resulting in inhibition of inflammation. Due to the role of PPARγ in macrophage polarization and anti-inflammation, PPARγ ligands have been used to treat metabolism-related inflammation and have shown significant anti-inflammatory therapeutic activity. Full agonist of PPARγ refers to a ligand which can bind to LBD domain with high-affinity and activate PPARγ thoroughly. For example, administration of pioglitazone, a full agonist of PPARγ, which can reduce the expression of IL-1β, IL-6, MCP-1, and TNF-α in peritoneal macrophages (Dasu et al., 2009), while rosiglitazone, another full agonist, upregulates the production of the anti-inflammatory molecule adiponectin, and thus decreases insulin resistance (Yang et al., 2002).