| RRC ID |
67312
|
| 著者 |
Real E, Rodrigues L, Cabal GG, Enguita FJ, Mancio-Silva L, Mello-Vieira J, Beatty W, Vera IM, Zuzarte-Luís V, Figueira TN, Mair GR, Mota MM.
|
| タイトル |
Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes.
|
| ジャーナル |
Nat Microbiol
|
| Abstract |
The causative agent of malaria, Plasmodium, replicates inside a membrane-bound parasitophorous vacuole (PV), which shields this intracellular parasite from the cytosol of the host cell 1 . One common threat for intracellular pathogens is the homeostatic process of autophagy, through which cells capture unwanted intracellular material for lysosomal degradation 2 . During the liver stage of a malaria infection, Plasmodium parasites are targeted by the autophagy machinery of the host cell, and the PV membrane (PVM) becomes decorated with several autophagy markers, including LC3 (microtubule-associated protein 1 light chain 3) 3,4 . Here we show that Plasmodium berghei parasites infecting hepatic cells rely on the PVM transmembrane protein UIS3 to avoid elimination by host-cell-mediated autophagy. We found that UIS3 binds host LC3 through a non-canonical interaction with a specialized surface on LC3 where host proteins with essential functions during autophagy also bind. UIS3 acts as a bona fide autophagy inhibitor by competing with host LC3-interacting proteins for LC3 binding. Our work identifies UIS3, one of the most promising candidates for a genetically attenuated vaccine against malaria 5 , as a unique and potent mediator of autophagy evasion in Plasmodium. We propose that the protein-protein interaction between UIS3 and host LC3 represents a target for antimalarial drug development.
|
| 巻・号 |
3(1)
|
| ページ |
17-25
|
| 公開日 |
2018-1-1
|
| DOI |
10.1038/s41564-017-0054-x
|
| PII |
10.1038/s41564-017-0054-x
|
| PMID |
29109477
|
| PMC |
PMC5739284
|
| MeSH |
Animals
Autophagosomes / metabolism
Autophagy / physiology*
Cell Line
HEK293 Cells
Hep G2 Cells
Hepatocytes / parasitology
Hepatocytes / pathology*
Hepatocytes / ultrastructure
Host-Pathogen Interactions
Humans
Malaria / parasitology*
Malaria / pathology*
Malaria / physiopathology
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins / metabolism*
Models, Molecular
Plasmodium berghei / genetics*
Plasmodium berghei / metabolism
Plasmodium berghei / pathogenicity
Protein Binding
Protozoan Proteins / genetics
Protozoan Proteins / metabolism
Vacuoles / metabolism
|
| IF |
15.54
|
| リソース情報 |
| ヒト・動物細胞 |
Atg5^(+/+)MEF(RCB2710)
Atg5^(-/-)MEF(RCB2711) |
