Familial
encephalopathy with
neuroserpin inclusions bodies (FENIB) is a serpinopathy that induces a rare form of
presenile dementia.
Neuroserpin contains a classical
signal peptide and like all extracellular
serine proteinase inhibitors (
serpins) is secreted via the endoplasmic reticulum (ER)-Golgi pathway. The disease phenotype is due to gain-of-function missense mutations that cause
neuroserpin to misfold and aggregate within the ER. In a previous study, nematodes expressing a homologous mutation in the endogenous Caenorhabditis elegans
serpin, srp-2, were reported to model the ER proteotoxicity induced by an allele of mutant
neuroserpin. Our results suggest that SRP-2 lacks a classical N-terminal
signal peptide and is a member of the intracellular
serpin family. Using confocal imaging and an ER colocalization marker, we confirmed that GFP-tagged wild-type SRP-2 localized to the cytosol and not the ER. Similarly, the aggregation-prone SRP-2 mutant formed intracellular inclusions that localized to the cytosol. Interestingly, wild-type SRP-2, targeted to the ER by fusion to a cleavable N-terminal
signal peptide, failed to be secreted and accumulated within the ER lumen. This ER retention phenotype is typical of other obligate intracellular
serpins forced to translocate across the ER membrane.
Neuroserpin is a secreted
protein that inhibits
trypsin-like
proteinase. SRP-2 is a cytosolic
serpin that inhibits lysosomal
cysteine peptidases. We concluded that SRP-2 is neither an ortholog nor a functional homolog of
neuroserpin. Furthermore, animals expressing an aggregation-prone mutation in SRP-2 do not model the ER proteotoxicity associated with FENIB.