Uptake of the Necrotic Serpin in Drosophila melanogaster via the Lipophorin Receptor-1
PLoS Genet. 2009-06-26; 5(6): e1000532
DOI: 10.1371/journal.pgen.1000532
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1. PLoS Genet. 2009 Jun;5(6):e1000532. doi: 10.1371/journal.pgen.1000532. Epub 2009
Jun 26.
Uptake of the necrotic serpin in Drosophila melanogaster via the lipophorin
receptor-1.
Soukup SF(1), Culi J, Gubb D.
Author information:
(1)Functional Genomics Unit, CIC bioGUNE, Derio, Spain.
The humoral response to fungal and Gram-positive infections is regulated by the
serpin-family inhibitor, Necrotic. Following immune-challenge, a proteolytic
cascade is activated which signals through the Toll receptor. Toll activation
results in a range of antibiotic peptides being synthesised in the fat-body and
exported to the haemolymph. As with mammalian serpins, Necrotic turnover in
Drosophila is rapid. This serpin is synthesised in the fat-body, but its site of
degradation has been unclear. By “freezing” endocytosis with a temperature
sensitive Dynamin mutation, we demonstrate that Necrotic is removed from the
haemolymph in two groups of giant cells: the garland and pericardial athrocytes.
Necrotic uptake responds rapidly to infection, being visibly increased after 30
mins and peaking at 6-8 hours. Co-localisation of anti-Nec with anti-AP50, Rab5,
and Rab7 antibodies establishes that the serpin is processed through
multi-vesicular bodies and delivered to the lysosome, where it co-localises with
the ubiquitin-binding protein, HRS. Nec does not co-localise with Rab11,
indicating that the serpin is not re-exported from athrocytes. Instead, mutations
which block late endosome/lysosome fusion (dor, hk, and car) cause accumulation
of Necrotic-positive endosomes, even in the absence of infection. Knockdown of
the 6 Drosophila orthologues of the mammalian LDL receptor family with dsRNA
identifies LpR1 as an enhancer of the immune response. Uptake of Necrotic from
the haemolymph is blocked by a chromosomal deletion of LpR1. In conclusion, we
identify the cells and the receptor molecule responsible for the uptake and
degradation of the Necrotic serpin in Drosophila melanogaster. The scavenging of
serpin/proteinase complexes may be a critical step in the regulation of
proteolytic cascades.
DOI: 10.1371/journal.pgen.1000532
PMCID: PMC2694266
PMID: 19557185 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.