Sending proteins to dense core secretory granules: still a lot to sort out

The intracellular sorting of peptide hormone precursors to the dense core secretory granules (DCSGs) is essential for their bioactivation. Despite the fundamental importance of this cellular process, the nature of the sorting signals for entry of proteins into DCSGs remains a source of vigorous debate. This review highlights recent discoveries that are consistent with a model in which several protein domains, acting in a cell-specific fashion and at different steps in the sorting process, act in concert to regulate the entry of proteins into DCSGs

Proteolytic processing of human prorenin in renal and non-renal tissues

Proteolytic processing of human prorenin in renal and non-renal tissues. Previous studies have demonstrated that the mouse proprotein convertase PC1 (mPC1) accurately cleaves human prorenin to generate active renin and that this processing event appears to require co-packaging in secretory granules. In the current study, we have tested human PC1 (hPC1; also called PC3) for its ability to activate human prorenin. Our results suggest that while hPC1 is capable of carrying out the specific cleavage of human prorenin, it does so at a reduced efficiency as compared to mPC1. This difference is due to sequences in the carboxy-terminus of PC1 as demonstrated by the activity of hybrid hPC1/mPC1 molecules. These studies demonstrate that PC1 cleavage of prorenin can occur in humans and identify a functionally important region in the hPC1 protein for this interaction. Moreover, the localization of PC1 in human tissues suggests that it may participate in the generation of active renin in the adrenal medulla and possibly in certain adrenal tumors

Evidence for intracellular generation of angiotensin II in rat juxtaglomerular cells

AbstractThe formation of the vasoactive peptide angiotensin II (AII) is dependent on the sequential action of two enzymes, renin and angiotensin converting enzyme (ACE), on the substrate angiotensinogen. Although the renin-producing cells of the kidney do not express angiotensinogen, they contain large amounts of AII in the same storage granules that contain renin. When renin expression is suppressed in these cells, AII also disappears. In the current study, we have tested whether the renin-associated disappearance of AII in renal juxtaglomerular (JG) cells is due to a renin-dependent down-regulation of granule biosynthesis and whether receptor-mediated internalization of AII could account for its concentration in these cells. Our results support a model whereby AII peptides are generated within JG cells, presumably by a mechanism which involves the action of endogenous renin on internalized, exogenous angiotensinogen