Abstract

   Arginylation  is  an  emerging  protein  modification  mediated  by
   arginyltransferase ATE1, shown to regulate  embryogenesis and actin
   cytoskeleton,  however  its  functions  in different  physiological
   systems are not well understood.  Here we analyzed the role of ATE1
   in brain development and neuronal growth by producing a conditional
   mouse knockout with Ate1 deletion in the  nervous  system driven by
   Nestin promoter (Nes-Ate1 mice).  These mice were  weaker than wild
   type,  resulting  in  low   postnatal   survival   rates,  and  had
   abnormalities  in  the  brain  that  suggested  defects in neuronal
   migration.  Cultured Ate1 knockout  neurons  showed  a reduction in
   the neurite outgrowth and the levels of doublecortin and F-actin in
   the growth cones.  In wild type, ATE1 prominently  localized to the
   growth cones, in addition to the cell  bodies.   Examination of the
   Ate1   mRNA   sequence   reveals   the    existence   of   putative
   zipcode-binding sequences involved in  mRNA  targeting  to the cell
   periphery and local translation at the  growth cones.  Fluorescence
   in situ hybridization showed that Ate1 mRNA  localized  to the tips
   of the growth cones, likely due to  zipcode-mediated targeting, and
   this  localization  coincided   with   spots   of  localization  of
   arginylated -actin, which disappeared  in  the  presence of protein
   synthesis   inhibitors.     We    propose   that   zipcode-mediated
   co-targeting  of  Ate1   and   -actin   mRNA   leads  to  localized
   co-translational arginylation of -actin that drives the growth cone
   migration and neurite outgrowth.

   (Developmental Biology, Volume 430(1), Page 41-51,
    doi:10.1016/j.ydbio.2017.08.027, 2017)