Proline Rich 7 (Prr7): An NMDA Receptor-Associated Synapto-Nuclear Protein Messenger in Control of c-Jun-Dependent Gene Transcription?

• Applicant: Dr. Michael R. Kreutz
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253297723

• Final Report Year: 2018

Final Report Abstract

The formation of long-term memories in the brain requires regulation of gene expression. In neurons different mechanisms have evolved to couple synaptic activity to gene transcription. Some of these signaling mechanisms need the transport of proteins from synapses to the nucleus. A particular rich source of synapto-nuclear protein messengers is the NMDA-receptor complex. Based on previous work we proposed to study the neuronal function of the transmembrane protein Prr7. Prr7 is a transmembrane adaptor protein and this protein family is well known in T-cell biology because they assemble a membrane proximal signalosome that is essential for TCR activation. However, we found that Prr7 has no essential function in the immune system where it is expressed only at very low levels. In the brain the protein is much more abundant and part of the NMDA-receptor complex where it binds the GluN1 subunit of NMDA receptors. We found that Prr7 is a synapto-nuclear protein messenger that following long-distance transport associates in the nucleus with the c-Jun complex and inhibits two key E3-ubiquitin ligases for ubiquitylation of c-Jun, Itch and FBW7. This mechanism is involved in NMDA-induced excitotoxicity. In addition, we found that Prr7 has a local synaptic function. Neurotropic virus infections, fever, as well as neurodegenerative disorders are often associated with production and release of the pro-inflammatory Interferon Gamma (IFN gamma). Collectively, published data show that activation of IFN gamma signaling and subsequent activation of its downstream target the transcription factor STAT1 negatively regulates memory and cognitive performance. In neurons STAT1 is abundant at synapses. We found that Prr7 is present in one complex with STAT1 and E3 ubiquitin ligases, and that Prr7 increases STAT1 ubiquitination and degradation. We further found that Prr7 plays an important role in protein ubiquitination at synapses and that it transduces inflammatory signals to local STAT signaling. This mechanism might mediate fever-induced impairment of cognitive function.

Publications

• Macromolecular transport in synapse to nucleus communication. Trends Neurosci. 2015 38(2):108-16
  Panayotis N, Karpova A, Kreutz MR, Fainzilber M
  
• A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis. PLoS Genet. 2016 12(3):e1005907
  Spilker C, Nullmeier S, Grochowska KM, Schumacher A, Butnaru I, Macharadze T, Gomes GM, Yuanxiang P, Bayraktar G, Rodenstein C, Geiseler C, Kolodziej A, Lopez- Rojas J, Montag D, Angenstein F, Bär J, D'Hanis W, Roskoden T, Mikhaylova M, Budinger E, Ohl FW, Stork O, Zenclussen AC, Karpova A, Schwegler H, Kreutz MR
  
• Normal Development and Function of T Cells in Proline Rich 7 (Prr7) Deficient Mice. PLoS One. 2016 11(9):e0162863
  Hrdinka M, Sudan K, Just S, Drobek A, Stepanek O, Schlüter D, Reinhold D, Jordan BA, Gintschel P, Schraven B, Kreutz MR
  
• Ring finger protein 10 is a novel synaptonuclear messenger encoding activation of NMDA receptors in hippocampus. Elife. 2016 5:e12430
  Dinamarca MC, Guzzetti F, Karpova A, Lim D, Mitro N, Musardo S, Mellone M, Marcello E, Stanic J, Samaddar T, Burguière A, Caldarelli A, Genazzani AA, Perroy J, Fagni L, Canonico PL, Kreutz MR, Gardoni F, Di Luca M
  
• Synaptic GluN2B/CaMKII-α Signaling Induces Synapto-Nuclear Transport of ERK and Jacob. Front Mol Neurosci. 2016 9:66
  Melgarejo da Rosa M, Yuanxiang P, Brambilla R, Kreutz MR, Karpova A
  
• Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. EMBO J. 2016 35(17):1923-34
  Kravchick DO, Karpova A, Hrdinka M, Lopez-Rojas J, Iacobas S, Carbonell AU, Iacobas DA, Kreutz MR, Jordan BA
  
• Posttranslational modification impact on the mechanism by which amyloid-β induces synaptic dysfunction. EMBO Rep. 2017 18(6):962- 981
  Grochowska KM, Yuanxiang P, Bär J, Raman R, Brugal G, Sahu G, Schweizer M, Bikbaev A, Schilling S, Demuth HU, Kreutz MR
  
• Caldendrin Directly Couples Postsynaptic Calcium Signals to Actin Remodeling in Dendritic Spines. Neuron. 2018 97(5):1110-1125.e14
  Mikhaylova M, Bär J, van Bommel B, Schätzle P, YuanXiang P, Raman R, Hradsky J, Konietzny A, Loktionov EY, Reddy PP, Lopez-Rojas J, Spilker C, Kobler O, Raza SA, Stork O, Hoogenraad CC, Kreutz MR