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Published on: June 13, 2014
Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1
David Lutz1, Gerrit Wolters-Eisfeld1, Gunjan Joshi1
1Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
Insights
The cell adhesion molecule L1 generates a 70-kDa fragment that moves to the nucleus, influencing nervous system development, regeneration, and neurodegeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Cell adhesion molecule L1 (L1) plays crucial roles in the nervous system through cell interactions.
- L1 signaling activates cellular responses via signal transduction pathways.
Purpose of the Study:
- To investigate the mechanism of L1-mediated signaling and the fate of L1 fragments.
- To determine the functional implications of a specific L1 fragment in the nervous system.
Main Methods:
- Stimulation of L1 signaling using function-triggering antibodies or L1-Fc.
- Analysis of L1 cleavage, fragment generation, and intracellular transport.
- Investigation of nuclear import pathways involving importin and chromatin-modifying protein 1.
- Site-directed mutagenesis to study the roles of sumoylation and nuclear localization signals.
Main Results:
- L1 stimulation induces serine protease-dependent cleavage, generating a sumoylated 70-kDa transmembrane fragment.
- This fragment is transported from the plasma membrane to late endosomes, then to the cytoplasm, and finally imported into the nucleus.
- Mutation of the sumoylation site (Lys1172) or nuclear localization signal (Lys1147) blocked fragment generation or nuclear import, respectively.
- Nuclear import of the 70-kDa fragment may activate cellular responses, potentially alongside phosphorylation-dependent pathways.
Conclusions:
- The 70-kDa intracellular fragment of L1 is generated and translocated to the nucleus via a specific pathway.
- This fragment's nuclear import is critical for L1-mediated cellular responses.
- Altered levels of the 70-kDa fragment in development, spinal cord injury, and Alzheimer's disease models suggest its involvement in neurodevelopment, regeneration, neurodegeneration, and synaptic plasticity.
Abstract:
The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys(1172) or of the nuclear localization signal at Lys(1147) abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system.
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