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Cytoplasmic phospholipase A2 antagonists inhibit multiple endocytic membrane trafficking pathways.

ABSTRACT: Previous studies have suggested a role for cytosolic Ca(2+)-independent phospholipase A(2) (PLA(2)) activity in the formation of endosome membrane tubules that participate in the export of transferrin (Tf) and transferrin receptors (TfR) from sorting endosomes (SEs) and the endocytic recycling compartment (ERC). Here we show that the PLA(2) requirement is a general feature of endocytic trafficking. The reversible cytoplasmic PLA(2) antagonist ONO-RS-082 (ONO) produced a concentration-dependent, differential block in the endocytic recycling of both low-density lipoprotein receptor (LDLR) and TfRs, and in the degradative pathways of LDL and epidermal growth factor (EGF). These results are consistent with the model that a cytoplasmic PLA(2) plays a general role in the export of cargo from multiple endocytic compartments by mediating the formation of membrane tubules.

SUBMITTER: Doody AM

PROVIDER: S-EPMC2764267 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Cytoplasmic phospholipase A2 antagonists inhibit multiple endocytic membrane trafficking pathways.

Doody Anne M AM Antosh Amy L AL Brown William J WJ

Biochemical and biophysical research communications 20090818 4

Previous studies have suggested a role for cytosolic Ca(2+)-independent phospholipase A(2) (PLA(2)) activity in the formation of endosome membrane tubules that participate in the export of transferrin (Tf) and transferrin receptors (TfR) from sorting endosomes (SEs) and the endocytic recycling compartment (ERC). Here we show that the PLA(2) requirement is a general feature of endocytic trafficking. The reversible cytoplasmic PLA(2) antagonist ONO-RS-082 (ONO) produced a concentration-dependent, ...[more]

PMID: 19695219

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Project description:Human NIMA-related kinases have primarily been studied for their roles in cell cycle progression (NEK1/2/6/7/9), checkpoint-DNA-damage control (NEK1/2/4/5/10/11), and ciliogenesis (NEK1/4/8). We previously showed that Caenorhabditis elegans NEKL-2 (NEK8/9 homolog) and NEKL-3 (NEK6/7 homolog) regulate apical clathrin-mediated endocytosis (CME) in the worm epidermis and are essential for molting. Here we show that NEKL-2 and NEKL-3 also have distinct roles in controlling endosome function and morphology. Specifically, loss of NEKL-2 led to enlarged early endosomes with long tubular extensions but showed minimal effects on other compartments. In contrast, NEKL-3 depletion caused pronounced defects in early, late, and recycling endosomes. Consistently, NEKL-2 was strongly localized to early endosomes, whereas NEKL-3 was localized to multiple endosomal compartments. Loss of NEKLs also led to variable defects in the recycling of two resident cargoes of the trans-Golgi network (TGN), MIG-14/Wntless and TGN-38/TGN38, which were missorted to lysosomes after NEKL depletion. In addition, defects were observed in the uptake of clathrin-dependent (SMA-6/Type I BMP receptor) and independent cargoes (DAF-4/Type II BMP receptor) from the basolateral surface of epidermal cells after NEKL-2 or NEKL-3 depletion. Complementary studies in human cell lines further showed that siRNA knockdown of the NEKL-3 orthologs NEK6 and NEK7 led to missorting of the mannose 6-phosphate receptor from endosomes. Moreover, in multiple human cell types, depletion of NEK6 or NEK7 disrupted both early and recycling endosomal compartments, including the presence of excess tubulation within recycling endosomes, a defect also observed after NEKL-3 depletion in worms. Thus, NIMA family kinases carry out multiple functions during endocytosis in both worms and humans, consistent with our previous observation that human NEKL-3 orthologs can rescue molting and trafficking defects in C. elegans nekl-3 mutants. Our findings suggest that trafficking defects could underlie some of the proposed roles for NEK kinases in human disease.

Dataset Information

Cytoplasmic phospholipase A2 antagonists inhibit multiple endocytic membrane trafficking pathways.

Publications

Cytoplasmic phospholipase A2 antagonists inhibit multiple endocytic membrane trafficking pathways.

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