Drosophila carboxypeptidase D (SILVER) is a key enzyme in neuropeptide processing required to maintain locomotor activity levels and survival rate

Neuropeptides are processed from larger preproproteins by a dedicated set
of enzymes. The molecular and biochemical mechanisms underlying
preproprotein processing and the functional importance of processing
enzymes are well‐characterised in mammals, but little studied outside this
group. In contrast to mammals, Drosophila melanogaster lacks a gene for
carboxypeptidase E (CPE), a key enzyme for mammalian peptide processing.
By combining peptidomics and neurogenetics, we addressed the role of
carboxypeptidase D (dCPD) in global neuropeptide processing and selected
peptide‐regulated behaviours in Drosophila. We found that a deficiency in
dCPD results in C‐terminally extended peptides across the peptidome,
suggesting that dCPD took over CPE function in the fruit fly. dCPD is
widely expressed throughout the nervous system, including peptidergic
neurons in the mushroom body and neuroendocrine cells expressing
adipokinetic hormone. Conditional hypomorphic mutation in the
dCPD‐encoding gene silver in the larva causes lethality, and leads to
deficits in starvation‐induced hyperactivity and appetitive gustatory
preference, as well as to reduced viability and activity levels in adults.
A phylogenomic analysis suggests that loss of CPE is not common to
insects, but only occurred in Hymenoptera and Diptera. Our results show
that dCPD is a key enzyme for neuropeptide processing and
peptide‐regulated behaviour in Drosophila. dCPD thus appears as a suitable
target to genetically shut down total neuropeptide production in
peptidergic neurons. The persistent occurrence of CPD in insect genomes
may point to important further CPD functions beyond neuropeptide
processing which cannot be fulfilled by CPE.