Lipid raft localization and palmitoylation: identification of two requirements for cell death induction by the tumor suppressors UNC5H.
UNC5H receptors (UNC5H1, UNC5H2, UNC5H3) are putative tumor suppressors whose expression is lost in numerous cancers. These receptors have been shown to belong to the so-called family of dependence receptors. Such receptors induce apoptosis when their ligand netrin-1 is absent, thus conferring a state of cellular dependence towards ligand presence. Along this line, these receptors may limit tumor progression because they induce the death of tumor cells that grow in settings of ligand unavailability. We show here that UNC5H receptors are localized to cholesterol-and sphingolipid-enriched membrane domains called lipid rafts. We then demonstrate that the lipid raft localization of UNC5H2 is required for the pro-apoptotic activity of unbound UNC5H2. We also propose that this lipid raft localization is probably mediated via the recruitment of adaptor protein(s) within the death domain of UNC5H2 but is not dependent on the post-translational modification by palmitoylation of UNC5H2 even though this palmitoylation is required for UNC5H2 pro-apoptotic activity. Moreover we show that the interaction of UNC5H2 with the downstream pro-apoptotic serine threonine kinase DAPk is dependent on both UNC5H2 lipid raft localization and palmitoylation. Thus, we propose that the UNC5H dependence receptors require lipid raft localization and palmitoylation to trigger apoptosis.
Maisse
Carine
C
Apoptosis, Cancer and Development Laboratory-Equipe Labellisée La Ligue, CNRS UMR5238, Université de Lyon, Centre Léon Berard, 69008 Lyon, France.
Rossin
Aurélie
A
Cahuzac
Nathalie
N
Paradisi
Andrea
A
Klein
Catherine
C
Haillot
Marie-Laure
ML
Hérincs
Zoltan
Z
Mehlen
Patrick
P
Hueber
Anne-Odile
AO
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D064550:Death-Associated Protein Kinases; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D000075386:Netrin Receptors; D019308:Palmitic Acid / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D019308:Palmitic Acid; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases