Makorin RING zinc-finger protein 1-dependent translational control of dendritic mRNAs in mammalian neurons
Final Report Abstract
Synaptic plasticity, the ability of brain synapses to strengthen or weaken over time and in response to changes in their activity, is one of the key neurochemical foundations for learning and memory in mammals. Certain forms of plasticity require local protein synthesis at synapses. In the past, we identified Makorin RING Finger Protein-1 short (MKRN1s) as a putative positive regulator of dendritic translation in nerve cells that may thus participate in the control of synaptic plasticity. Central aim of this work was to better understand the molecular mode of action for MKRN1s and more general its significance for RNA metabolism. Thus, we determined that the first zinc finger (ZF1) and the PAM2 motif, which mediates an association with the poly(A) binding protein (PABP), are required for the stimulatory effect of MKRN1s upon translation in neurons as well as its recruitment into so-called stress granules. The later are cytoplasmic assemblies, in which mRNA/protein complexes are transiently removed from translation whenever cells are exposed to stressful conditions. These findings implicate that ZF1 and PAM2 are essential for MKRN1s’ ability to both associate with and control the activity of translation complexes in brain neurons. Biochemical purification of MKRN1s containing complexes from cultured cells and identification of their protein components showed that these in vivo assemblies contain a rather large variety of proteins that have been implicated in different steps of RNA metabolism. Of these the La-related protein 1 (LARP1) and UPF1 (regulator of nonsense transcripts 1) represent novel and prominent MKRN1s interaction partners. The PAM2 motif in MKRN1s is essential for its association with these two proteins, while binding of the La module in LARP1 to the four RNA recognition motifs (RRMs) in PABP mediates an indirect association of LARP1 with MKRN1s. On the functional level, interaction of MKRN1s with both LARP1 and UPF1 appears to be required for its ability to stimulate mRNA translation in neurons. Finally, we show that MKRN1s also interacts with the translation initiation complex eIF4F in a PABP-dependent manner. Taken together, these and additional published findings suggest that in neurons MKRN1s associates with LARP1, UPF1 and PABP to regulate translation initiation in neurons, including local translational control at synapses.
Publications
- (2014) A non-canonical initiation site is required for efficient translation of the dendritically localized Shank1 mRNA. PLoS One 9, e88518
Studtmann, K., Olschläger-Schütt, J., Buck, F., Richter, D., Sala, C., Bockmann, J., Kindler, S., Kreienkamp, H.-J.
(See online at https://doi.org/10.1371/journal.pone.0088518) - (2014) Nedd4-2 regulates surface expression and may affect N-glycosylation of hyperpolarizationactivated cyclic nucleotide-gated (HCN)-1 channels. FASEB J. 28, 2177
Wilkars, W., Wollberg, J., Mohr, E., Han, M., Chetkovich, D. M., Bähring, R., Bender, R. A.
(See online at https://doi.org/10.1096/fj.13-242032) - (2016) Inositol-1,4,5-trisphosphate-3-kinase-A controls morphology of hippocampal dendritic spines. Cell Signal 28, 83
Köster, J.D., Leggewie, B., Blechner, C., Brandt, N., Fester, L., Rune, G., Schweizer, M., Kindler, S., Windhorst, S.
(See online at https://doi.org/10.1016/j.cellsig.2015.10.016) - (2016) Shank3 is part of a zinc-sensitive signaling system that regulates excitatory synaptic strength. J Neurosci 36, 9124
Arons, M. H., Lee, K., Thynne, C. J., Kim, S. A., Schob, C., Kindler, S., Montgomery, J. M., and Garner, C. C.
(See online at https://doi.org/10.1523/JNEUROSCI.0116-16.2016) - (2017) De novo missense mutations in DHX30 impair global translation and cause a neurodevelopmental disorder. Am J Hum Genet 101, 716
Lessel, D., Schob, C., Kury, S., Reijnders, M. R. F., Harel, T., Eldomery, M. K., Coban-Akdemir, Z., Denecke, J., Edvardson, S., Colin, E., Stegmann, A. P. A., Gerkes, E. H., Tessarech, M., Bonneau, D., Barth, M., Besnard, T., Cogne, B., Revah-Politi, A., Strom, T. M., Rosenfeld, J. A., Yang, Y., Posey, J. E., Immken, L., Oundjian, N., Helbig, K. L., Meeks, N., Zegar, K., Morton, J., study, D. D. D., Schieving, J. H., Claasen, A., Huentelman, M., Narayanan, V., Ramsey, K., Group, C. R. R., Brunner, H. G., Elpeleg, O., Mercier, S., Bezieau, S., Kubisch, C., Kleefstra, T., Kindler, S., Lupski, J. R., and Kreienkamp, H. J.
(See online at https://doi.org/10.1016/j.ajhg.2017.09.014) - (2019) Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice. Transl Psychiatry 9, 7
Schob, C., Morellini, F., Ohana, O., Bakota, L., Hrynchak, M. V., Brandt, R., Brockmann, M. D., Cichon, N., Hartung, H., Hanganu-Opatz, I. L., Kraus, V., Scharf, S., Herrmans-Borgmeyer, I., Schweizer, M., Kuhl, D., Wohr, M., Vorckel, K. J., Calzada-Wack, J., Fuchs, H., Gailus-Durner, V., Hrabe de Angelis, M., Garner, C. C., Kreienkamp, H. J., and Kindler, S.
(See online at https://doi.org/10.1038/s41398-018-0327-z)
