Abstract
The protein phosphatase 1-like gene (PPM1l) was identified as causal gene for obesity and metabolic abnormalities in mice. However, the underlying mechanisms were unknown. In this report, we find PPM1l encodes an endoplasmic reticulum (ER) membrane targeted protein phosphatase (PP2Ce) and has specific activity to basal and ER stress induced auto-phosphorylation of Inositol-REquiring protein-1 (IRE1). PP2Ce inactivation resulted in elevated IRE1 phosphorylation and higher expression of XBP-1, CHOP, and BiP at basal. However, ER stress stimulated XBP-1 and BiP induction was blunted while CHOP induction was further enhanced in PP2Ce null cells. PP2Ce protein levels are significantly induced during adipogenesis in vitro and are necessary for normal adipocyte maturation. Finally, we provide evidence that common genetic variation of PPM11 gene is significantly associated with human lipid profile. Therefore, PPM1l mediated IRE1 regulation and downstream ER stress signaling is a plausible molecular basis for its role in metabolic regulation and disorder.
Highlights
Metabolic syndrome is a major risk factor for diabetes, cardiovascular diseases and cancer
In order to investigate the molecular mechanisms of inositol-requiring protein-1 (IRE1) regulation and function, the IRE1 signaling complex was isolated from a pancreatic insulinoma INS-1 cell line expressing an IRE1 dominant-negative mutant (IRE1α-K599A) fused with both FLAG and HA epitopes at its carboxyl terminus by binding to anti-FLAG and anti-HA immunoaffinity columns
Among the uncharacterized IRE1 interacting proteins, we identified the product of the Ppml1 gene based on extensive peptide coverage (Supplemental Figure 1A)
Summary
Metabolic syndrome is a major risk factor for diabetes, cardiovascular diseases and cancer. Using a systems-based co-expression network analysis in mice, Chen et al [1] has identified a number of sub-networks that are significantly associated with metabolic syndrome and obesity. Among the genes identified in this study, the Ppm gene was shown to exhibit a significant causal effect on obesity based on statistical modeling. This finding highlights the power of an unbiased systems genetics approach to uncover novel genes associated with complex phenotypic traits relevant to human diseases. We employed a comprehensive set of experimental tools, including proteomics, cell biology and genetic analyses, to uncover the molecular basis and the functional relevance of the Ppml gene product. Our results indicate that the Ppml gene encodes an endoplasmic reticulum (ER) targeted protein phosphatase with high specificity for an ER membrane localized kinase/ endoribonuclease inositol-requiring protein-1 (IRE1), a key regulator in the ER stress signaling pathway
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