HepaCAM associates with connexin 43 and enhances its localization in cellular junctions.
HepaCAM (GlialCAM) is frequently deleted in carcinomas, and reintroduction of hepaCAM into transformed cell lines reduces cellular growth and induces senescence. Mutations in HEPACAM give rise to the neurodegenerative disease megalencephalic leukoencephalopathy with subcortical cysts (MLC) since mutated hepaCAM prevents shuttling of MLC1 protein to astrocytic junctions in the plasma membrane. Here we identify that hepaCAM associates with connexin 43, a main component of gap junctions, and enhances connexin 43 localization to the plasma membrane at cellular junctions. HepaCAM also increases the levels of connexin 43, not by enhancing its transcription but by stabilizing connexin 43 protein. In the absence of hepaCAM, connexin 43 undergoes a faster degradation via the lysosomal pathway while proteasomal degradation seems not to be involved. Mutations in hepaCAM that cause MLC, or neutralization of hepaCAM by antibodies disrupt its association with connexin 43 at cellular junctions. By discovering the requirement of hepaCAM for localizing connexin 43, a well-established tumor suppressor, to cellular junctions and stabilizing it there, this study suggests a mechanism by which deletion of hepaCAM may support tumor progression.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456.
Meihui
M
Wu
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456.
Mei Chung
MC
Moh
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456.
Herbert
H
Schwarz
D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D018031:Connexin 43; C487620:HEPACAM protein, human; D011506:Proteins; D025521:Tumor Suppressor Proteins