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• W2040758091 abstract "In 2008, a group from Merck & Co reported the development of an alternative approach to classical forward genetics for dissecting complex disease traits [1]. The methodology is complex, but in essence, instead of identifying susceptibility genes directly affected by variations in DNA, they identified gene networks that are perturbed by susceptibility loci, which in turn could lead to disease. When they applied this method to liver and adipose gene expression data generated from a segregating mouse population, a macrophage-enriched network was found to have a ‘causal relationship’ with disease traits associated with the metabolic syndrome. One of the genes within this network was identified as Ppm1l, which encoded a then poorly characterized protein phosphatase [1].Fast forward to 2013, and in this issue of Molecular Metabolism, Lu et al. report a detailed characterization of the protein product of Ppm1l, which they christened ‘protein phosphatase 2C on endoplasmic reticulum’ or PP2Ce [2]. They propose that PP2Ce is a specific phosphatase for inositol requiring-protein 1 (IRE1), a serine/threonine protein kinase that alters gene expression as a response to endoplasmic reticulum based stress signals. In ER stress signaling, three sentinel proteins, IRE1, ATF6, and PERK detect a deficiency in ER function and via their signaling pathways enable the cell to adapt to metabolic perturbation and/or altered secretory requirements, in an attempt to restore homeostasis (Figure 1) (reviewed by [3]). Based on their findings published herein, the authors suggest that PP2Ce regulates the functional outcome of the ER stress response [2]. Given the major role that ER stress signaling plays in the normal physiology of multiple organs, particularly in those endocrine tissues that have a major load of protein translation and secretion, this is quite a bold statement that bears closer scrutiny.Figure 1The ER organelle plays a crucial role in cell homeostasis and survival. Alteration in ER homeostasis due to increased protein secretion, accumulation of misfolded proteins or alterations in the calcium or redox balance of the ER leads to a process called ...It was while using a proteomic approach to identify molecular components of the IRE1 signaling complex that Lu and colleagues stumbled upon PP2Ce. Using a combination of standard transfection, immunofluorescence and co-immunoprecipitation studies, the authors put forth a strong case that PP2Ce interacts with IRE1 within the ER, and also present convincing evidence for PP2Ce having phosphatase activity at IRE1.The crux of the paper however, focusses on attempts to link the function of PP2Ce to metabolic traits, which was after all, how the protein was identified to begin with. Here the authors show that PP2Ce expression is induced during the later stages of adipocyte differentiation and sustained in mature adipocytes. When PP2Ce expression is knocked-down in 3T3L1 cells, they show that this leads to defective adipogenesis, leading the authors to suggest that PP2Ce affects the dynamic regulation of the UPR during adipocyte differentiation [2]. These data however have inconsistencies with previously published work.There is certainly clear evidence that ER stress pathways are involved in regulating adipocyte differentiation. Induction of ER stress can inhibit the differentiation of fat and CHOP was identified as a key ER stress induced transcription factor that regulated adipogenesis in response to metabolic stress [4,5]. Most importantly, these findings are physiologically relevant since mice lacking CHOP exhibit increased fat mass compared to wildtype counterparts when fed on a high fat diet [4]. Data from Batchvarova et al. suggests that CHOP interferes with the accumulation of adipogenic C/EBP isoforms [4]. Actually, considering the ‘weight’ of evidence that suggests that the ER stress/PERK arm regulates adipocyte differentiation it is surprising that the natural target of PP2CE is not PERK, but IRE1.There is however, contradictory evidence on whether the IRE-1/XBP-1 arm of the ER stress response modulates adipogenesis. In a study invoked by Lu and colleagues, Sha et al. have shown that IRE1 and XBP-1 are required for adipocyte differentiation, and that spliced XBP-1 can rescue the adipogenic defect exhibited by XBP-1 deficient cells [6]. In contrast, Han et al. dispute that IRE1 contributes any significant signals to differentiating adipocytes, revealing that neither enforced expression of IRE1, which induced XBP-1 splicing, nor expression of a dominant negative IRE-1 in 3T3-L1 cell lines, had any effect on their differentiation [5]. More recently, the finding that deletion of XBP-1 in adipocytes in vivo did not inhibit adipogenesis in mice fed on a normal or high fat diet [7], raises the question whether PP2ce activity on IRE1 and its attendant XBP-1 splicing is the crucial pathway by which loss of PP2Ce modulates adipocyte differentiation. There was however an interesting exception, whereby lactating females exhibited greater adipogenesis in the absence of XBP-1, suggesting adipocyte development may be susceptible to inhibition by XBP-1 when certain developmental signals are present [7]. It should also be noted IRE1 can induce additional signaling pathways to XBP-1 splicing including JNK activation, and these may be critical in modulating adipogenesis in vivo.Additionally, although the authors suggest that the knockdown of PP2Ce results in a significant reduction in adipocyte differentiation, this data does not dovetail neatly with the phenotype of mice lacking PP2Ce [1]. There is undoubtedly clear evidence for PP2Ce in the regulation of body-weight with Ppm1l−/− mice weighing 19.3% more than wild-type mice; however, it appears that a targeted deletion of Ppm1l actually leads to a 46.7% increase in fat mass at 20 weeks of age [1]. One must consider whether the adipocyte differentiation phenotype reported here is actually physiologically relevant or is it perhaps an artefact of the in vitro methodology?Finally, the authors also repeatedly state here that PP2Ce has specific activity towards IRE1. As we mention above, the case for PP2Ce acting as a phosphatase on IRE1 is strong indeed. What is not addressed here however is what other targets PP2Ce would act upon, and whether it is the dysregulation of these unknown targets that play the primary role in the adipocyte differentiation phenotype?We do believe that this study is very interesting and will undoubtedly be of value to the field. However, before passing judgement on the physiological relevance of these findings, more work will need to be done to determine PP2Ce's promiscuity (or not) as a phosphatase, which would also do much to clarify the contradictory evidence of PP2Ce's role (or not) in adipogenesis." @default.
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• W2040758091 date "2013-11-01" @default.
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• W2040758091 title "PP2Ce: Fat and stressed out?" @default.
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• W2040758091 doi "https://doi.org/10.1016/j.molmet.2013.08.009" @default.
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