LAPTM4B facilitates late endosomal ceramide export to control cell death pathways.
Lysosome-associated protein transmembrane-4b (LAPTM4B) associates with poor prognosis in several cancers, but its physiological function is not well understood. Here we use novel ceramide probes to provide evidence that LAPTM4B interacts with ceramide and facilitates its removal from late endosomal organelles (LEs). This lowers LE ceramide in parallel with and independent of acid ceramidase-dependent catabolism. In LAPTM4B-silenced cells, LE sphingolipid accumulation is accompanied by lysosomal membrane destabilization. However, these cells resist ceramide-driven caspase-3 activation and apoptosis induced by chemotherapeutic agents or gene silencing. Conversely, LAPTM4B overexpression reduces LE ceramide and stabilizes lysosomes but sensitizes to drug-induced caspase-3 activation. Together, these data uncover a cellular ceramide export route from LEs and identify LAPTM4B as its regulator. By compartmentalizing ceramide, LAPTM4B controls key sphingolipid-mediated cell death mechanisms and emerges as a candidate for sphingolipid-targeting cancer therapies.
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Tomas
T
Blom
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Shiqian
S
Li
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Andrea
A
Dichlberger
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Nils
N
Bäck
Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, New York, USA.
Young Ah
YA
Kim
Department of Biochemistry, University of Geneva, CH-1211 Geneva 4, Switzerland.
Ursula
U
Loizides-Mangold
Department of Biochemistry, University of Geneva, CH-1211 Geneva 4, Switzerland.
Howard
http://orcid.org/0000-0003-4680-9422
H
Riezman
Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, New York, USA.
Robert
R
Bittman
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Elina
E
Ikonen
D018943:Anthracyclines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D013109:Sphingomyelins / Q000378:metabolism
D018943:Anthracyclines; D000970:Antineoplastic Agents; D002518:Ceramides; C477083:LAPTM4B protein, human; D008565:Membrane Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D013109:Sphingomyelins; D017239:Paclitaxel