Generation and Nuclear Translocation of Sumoylated Transmembrane Fragment of Cell Adhesion Molecule L1

JBC, 2012 · DOI: 10.1074/jbc.M112.346759 · Published: May 18, 2012

Simple Explanation

The cell adhesion molecule L1 is important for the nervous system's development and function. The study found that stimulating L1 causes it to be modified by a process called sumoylation and then cut into fragments. One of these fragments, a transmembrane piece, moves into the cell's nucleus. This movement to the nucleus and the sumoylation modification are important for L1 to do its job. Understanding these processes can help us understand disorders linked to L1. 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.

Study Duration

Not specified

Participants

Mice, cerebellar neurons, SH-SY5Y cells, HEK293TN cells

Evidence Level

Not specified

Key Findings

1
L1 stimulation leads to the generation of a 70-kDa transmembrane fragment that is translocated to the nucleus.
2
Sumoylation of L1 at Lys1172 is a prerequisite for the extracellular proteolytic cleavage of L1 and the generation of the 70-kDa fragment
3
Nuclear import of the 70-kDa fragment depends on importin and is associated with import of CHMP1 into nucleus.

Research Summary

The neural cell adhesion molecule L1 plays crucial roles during development of the nervous system, such as neuronal migration and survival, axon outgrowth and fasciculation, and myelination, but it is also involved in functions of the adult brain, such as synaptic plasticity, learning, and memory as well as regeneration after central and peripheral nervous system trauma Stimulation of L1 signaling triggers attachment of one SUMO molecule to the full-length 200-kDa L1. Extracellular serine protease-dependent cleavage of the sumoylated L1 results in the generation of a soluble extracellular 135-kDa fragment and a transmembrane 70-kDa fragment containing the intracellular domain and part of the extracellular domain. Nuclear import of the 70-kDa fragment depends on importin and is associated with import of CHMP1 into nucleus. Generation of 70-kDa Fragment Correlates with Brain Development, Regeneration after Spinal Cord Injury, and Degeneration in Alzheimer Disease Mouse Model

Practical Implications

Understanding L1-linked disorders

Unraveling the molecular mechanisms underlying L1-activated cellular responses helps understanding L1-linked disorders.

Targeted Therapies

Identifying specific proteases involved in L1 cleavage could lead to targeted therapies for neurological disorders.

Drug Development

Modulating L1 sumoylation and nuclear translocation pathways may offer novel drug targets.

Study Limitations

1
The specific serine protease responsible for L1 cleavage remains unknown.
2
The exact functional role of the 70-kDa fragment in the nucleus is not fully elucidated.
3
The study relies on in vitro and animal models, and further research is needed to confirm these findings in humans.

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