@article{LinderHirmerGaletal.2014,
  author    = {Linder, Bastian and Hirmer, Anja and Gal, Andreas and R{\"u}ther, Klaus and Bolz, Hanno J{\"o}rn and Winkler, Christoph and Laggerbauer, Bernhard and Fischer, Utz},
  title     = {Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa},
  doi       = {10.1371/journal.pone.0111754},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113663},
  year      = {2014},
  abstract  = {Pre-mRNA splicing by the spliceosome is an essential step in the maturation of nearly all human mRNAs. Mutations in six spliceosomal proteins, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, cause retinitis pigmentosa (RP), a disease characterized by progressive photoreceptor degeneration. All splicing factors linked to RP are constituents of the U4/U6.U5 tri-snRNP subunit of the spliceosome, suggesting that the compromised function of this particle may lead to RP. Here, we report the identification of the p.R192H variant of the tri-snRNP factor PRPF4 in a patient with RP. The mutation affects a highly conserved arginine residue that is crucial for PRPF4 function. Introduction of a corresponding mutation into the zebrafish homolog of PRPF4 resulted in a complete loss of function in vivo. A series of biochemical experiments suggested that p.R192H disrupts the binding interface between PRPF4 and its interactor PRPF3. This interferes with the ability of PRPF4 to integrate into the tri-snRNP, as shown in a human cell line and in zebrafish embryos. These data suggest that the p.R192H variant of PRPF4 represents a functional null allele. The resulting haploinsufficiency of PRPF4 compromises the function of the tri-snRNP, reinforcing the notion that this spliceosomal particle is of crucial importance in the physiology of the retina.},
  language  = {en}
}
@article{RegnLaggerbauerJentzschetal.2016,
  author    = {Regn, Michael and Laggerbauer, Bernhard and Jentzsch, Claudia and Ramanujam, Deepak and Ahles, Andrea and Sichler, Sonja and Calzada-Wack, Julia and Koenen, Rory R. and Braun, Attila and Nieswandt, Bernhard and Engelhardt, Stefan},
  title     = {Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium},
  series = {Journal of Molecular and Cellular Cardiology},
  volume    = {99},
  journal   = {Journal of Molecular and Cellular Cardiology},
  doi       = {10.1016/j.yjmcc.2016.08.010},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187039},
  pages     = {57-64},
  year      = {2016},
  abstract  = {A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol (-GPI) membrane anchor. Based on a reported genetic association of PI16 and plasma levels of the chemokine chemerin, we investigated whether PI16 regulates post-translational processing of its precursor pro-chemerin. PI16-deficient mice were engineered and found to generate higher levels of processed chemerin than wildtype mice. Purified recombinant PI16 efficiently inhibited cathepsin K, a chemerin-activating protease, in vitro. Moreover, we show that conditioned medium from PI16-overexpressing cells impaired the activation of pro-chemerin. Together, our data indicate that PI16 suppresses chemerin activation in the myocardium and suggest that this circuit may be part of the cardiac stress response.},
  language  = {en}
}