Abstract
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, which plays critical roles in a wide spectrum of neuronal functions including neuronal survival, neurite outgrowth, and synapse development and plasticity. Cdk5 activity is controlled by its specific activators: p35 or p39. While knockout studies reveal that Cdk5/p35 is critical for neuronal migration during early brain development, functions of Cdk5/p35 have been unraveled through the identification of the interacting proteins of p35, most of which are Cdk5/p35 substrates. However, it remains unclear whether p35 can regulate neuronal functions independent of Cdk5 activity. Here, we report that a nuclear protein, nuclear hormone receptor coregulator (NRC)-interacting factor 1 (NIF-1), is a new interacting partner of p35. Interestingly, p35 regulates the functions of NIF-1 independent of Cdk5 activity. NIF-1 was initially discovered as a transcriptional regulator that enhances the transcriptional activity of nuclear hormone receptors. Our results show that p35 interacts with NIF-1 and regulates its nucleocytoplasmic trafficking via the nuclear export pathway. Furthermore, we identified a nuclear export signal on p35; mutation of this site or blockade of the CRM1/exportin-dependent nuclear export pathway resulted in the nuclear accumulation of p35. Intriguingly, blocking the nuclear export of p35 attenuated the nuclear accumulation of NIF-1. These findings reveal a new p35-dependent mechanism in transcriptional regulation that involves the nucleocytoplasmic shuttling of transcription regulators.
Highlights
Neural development in response to various stimuli such as neural activity, neurotrophic factors, and nuclear hormones is a tightly coordinated process that involves the concerted regulation of gene expression [1,2]
Blocking the chromosome region maintenance 1 (CRM1)-dependent nuclear export pathway by LMB resulted in significant accumulation of p35 in the nuclei of neurons while the total expression of p35 remained relatively unchanged (Fig. 4E). These findings collectively suggest that the CRM1-dependent pathway is responsible for the nuclear export of p35 in neurons, Figure 1. p35 interacts with Nuclear Hormone Receptor Coregulator-Interacting Factor 1 (NIF-1). (A) Mouse NIF-1 encodes a 1,291-amino acid protein and contains 6 zinc finger domains, an LXXLL domain, and a leucine zipper-like motif. (B & C) Mapping of interaction domains between NIF-1 and p35
The present study identified a new mechanism of p35 wherein it regulates nuclear functions through modulating the nuclear accessibility of the transcriptional regulator NIF-1
Summary
Neural development in response to various stimuli such as neural activity, neurotrophic factors, and nuclear hormones is a tightly coordinated process that involves the concerted regulation of gene expression [1,2]. The nucleocytoplasmic shuttling of negative transcriptional regulator class II histone deacetylases in response to neural activity is important for the regulation of gene expression during neuronal differentiation and synaptogenesis [3]. The precise mechanisms regulating the nuclear accessibility of transcriptional complexes in neurons, including post-translational modifications such as protein phosphorylation/dephosphorylation and protein– protein interactions, remain largely unknown. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/ threonine kinase It has two neuronal-specific Cdk activators, p35 and p39 [4], whose associations with Cdk are essential for the activity of the kinase. The functions of Cdk5/p35 have been uncovered through the identification of the substrates of Cdk, most of which were first identified to interact with p35 [8]
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