title: PPM1l encodes an inositol requiring-protein 1 (IRE1) specific phosphatase that regulates the functional outcome of the ER stress response.
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.
authors: Departments of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors: Gang
authors: G
authors: Lu
authors: Asuka
authors: A
authors: Ota
authors: Shuxun
authors: S
authors: Ren
authors: Sarah
authors: S
authors: Franklin
authors: Christoph D
authors: CD
authors: Rau
authors: Peipei
authors: P
authors: Ping
authors: Timothy F
authors: TF
authors: Lane
authors: Z Hong
authors: ZH
authors: Zhou
authors: Karen
authors: K
authors: Reue
authors: Aldons J
authors: AJ
authors: Lusis
authors: Thomas
authors: T
authors: Vondriska
authors: Yibin
authors: Y
authors: Wang
keywords: Adipogenesis; ER stress; IRE1; PPM1l; Protein phosphatase