Amyloid-like aggregation of provasopressin in diabetes insipidus and secretory granule sorting

Abstract

BackgroundAggregation of peptide hormone precursors in the trans-Golgi network is an essential process in the biogenesis of secretory granules in endocrine cells. It has recently been proposed that this aggregation corresponds to the formation of functional amyloids. Our previous finding that dominant mutations in provasopressin, which cause cell degeneration and diabetes insipidus, prevent native folding and produce fibrillar aggregates in the endoplasmic reticulum (ER) might thus reflect mislocalized amyloid formation by sequences that evolved to mediate granule sorting.ResultsHere we identified two sequences responsible for fibrillar aggregation of mutant precursors in the ER: the N-terminal vasopressin nonapeptide and the C-terminal glycopeptide. To test their role in granule sorting, the glycopeptide was deleted and/or vasopressin mutated to inactivate ER aggregation while still permitting precursor folding and ER exit. These mutations strongly reduced sorting into granules and regulated secretion in endocrine AtT20 cells.ConclusionThe same sequences — vasopressin and the glycopeptide — mediate physiological aggregation of the wild-type hormone precursor into secretory granules and the pathological fibrillar aggregation of disease mutants in the ER. These findings support the amyloid hypothesis for secretory granule biogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0347-9) contains supplementary material, which is available to authorized users.

Mice deficient for ERAD machinery component Sel1L develop central diabetes insipidus

“…Both WT and some human proAVP mutants were shown to be substrates of Sel1L-Hrd1 ERAD. In Sel1L-null N2a cells, both WT and mutant proAVP appeared to accumulate in amyloid-like fibrillar structures, similar to what has been previously observed for human AVP mutants (10).…”

“…In mammals, the most well-characterized ERAD machinery is the highly conserved complex of suppressor-enhancer of lin-12-like and hydroxymethylglutaryl-CoA reductase degradation protein 1 (SEL1L-HRD1), which consists of the E3 ubiquitin ligase HRD1 and its adaptor protein SEL1Lc ( Figure 1B). In this issue Shi et al (10). Both WT and some human proAVP mutants were shown to be substrates of Sel1L-Hrd1 ERAD.…”

ICA512 RESP18 homology domain is a protein-condensing factor and insulin fibrillation inhibitor

“…While the detailed mechanism of proprotein sorting into SGs is not well established, it is clear that signal-mediated sorting and congregation-aggregation of regulated cargoes contribute to the biogenesis of SGs (25)(26)(27)(28).…”

Amyloid‐like aggregation of designer bolaamphiphilic peptides: Effect of hydrophobic section and hydrophilic heads

“…2,3 On the other hand, it has been found that a variety of nonpathogenic proteins could also form amyloid fibrils with normal biological functions, indicating that formation of amyloid fibrils is a prevailing phenomenon in nature. [4][5][6] Amyloidogenic proteins or polypeptides usually came from different tissues and showed very little similarity considering their full amino acid sequences, but the amyloid fibrils they formed shared several characteristic features such as similar morphology, apple-green birefringence after Congo red (CR) staining, and specific fluorescence when binding with thioflavin-T (ThT), suggesting that there might be a common mechanism for the formation of amyloid fibrils by these different proteins or polypeptides.…”