Abstract
The endoplasmic reticulum (ER), as a multifunctional organelle, plays crucial roles in lipid biosynthesis and calcium homeostasis as well as the synthesis and folding of secretory and membrane proteins. Therefore, it is of high importance to maintain ER homeostasis and to adapt ER function and morphology to cellular needs. Here, we show that signal peptide peptidase (SPP) modulates the ER shape through degradation of morphogenic proteins. Elevating SPP activity induces rapid rearrangement of the ER and formation of dynamic ER clusters. Inhibition of SPP activity rescues the phenotype without the need for new protein synthesis, and this rescue depends on a pre-existing pool of proteins in the Golgi. With the help of organelle proteomics, we identified certain membrane proteins to be diminished upon SPP expression and further show that the observed morphology changes depend on SPP-mediated cleavage of ER morphogenic proteins, including the SNARE protein syntaxin-18. Thus, we suggest that SPP-mediated protein abundance control by a regulatory branch of ER-associated degradation (ERAD-R) has a role in shaping the early secretory pathway.
Highlights
The endoplasmic reticulum (ER), as a multifunctional organelle, plays crucial roles in lipid biosynthesis and calcium homeostasis as well as the synthesis and folding of secretory and membrane proteins
With the help of organelle proteomics, we identified certain membrane proteins to be diminished upon signal peptide peptidase (SPP) expression and further show that the observed morphology changes depend on SPP-mediated cleavage of ER morphogenic proteins, including the soluble NSF attachment protein receptor (SNARE) protein syntaxin-18
The so-called trans-SNARE complex between vesicle and target membrane induces specificity and lowers the energy barrier of membrane fusion [11], there is growing evidence that chored; STX, syntaxin; SILAC, stable isotope labeling with amino acids in cell culture; Z, benzyloxycarbonyl; EndoH, endoglycosidase H; PNGaseF, peptide:N-glycosidase F; RFP, red fluorescent protein; OSER, organized smooth ER; IRES, internal ribosomal entry site; STED, stimulated emission depletion; CLEM, correlative light and EM; PKC, protein kinase C; CFP, cyan fluorescent protein; GalT, galactosyltransferase; NA, numerical aperture; LM, light microscopy; HA, hemagglutinin; SPP-DA, SPP-D265A
Summary
The endoplasmic reticulum (ER), as a multifunctional organelle, plays crucial roles in lipid biosynthesis and calcium homeostasis as well as the synthesis and folding of secretory and membrane proteins. The authors declare that they have no conflicts of interest with the contents of this article. This is mainly achieved by controlled vesicle budding from one compartment followed by intracellular transport and coordinated fusion of the transport vesicle with the target organelle. Major players in this process that ensure selectivity of the fusion step are soluble NSF attachment protein receptor (SNARE) proteins. SPP cleaves syntaxin-18 certain SNAREs play a role in organelle morphology control, including cell cycle– dependent ER rearrangement, homotypic membrane fusion, and organization of the ER network [13,14,15,16]
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