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The intramembrane protease SPP impacts morphology of the endoplasmic reticulum by triggering degradation of morphogenic proteins.

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.

SUBMITTER: Avci D

PROVIDER: S-EPMC6393608 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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The intramembrane protease SPP impacts morphology of the endoplasmic reticulum by triggering degradation of morphogenic proteins.

Avci Dönem D Malchus Nicole S NS Heidasch Ronny R Lorenz Holger H Richter Karsten K Neßling Michelle M Lemberg Marius K MK

The Journal of biological chemistry 20181221 8

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 ...[more]

PMID: 30578301

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Project description:Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), rely heavily on the availability of endoplasmic reticulum (ER) membranes throughout their life cycle, and degradation of ER membranes restricts flavivirus replication. Accordingly, DENV and ZIKV restrict ER turnover by protease-mediated cleavage of reticulophagy regulator 1 (RETREG1), also known as FAM134B, an autophagy receptor responsible for targeted ER sheet degradation. Given that the induction of autophagy may play an important role in flavivirus replication, the antiviral role of RETREG1 suggests that specialized autophagic pathways may have differential effects on the flavivirus life cycle. We previously identified BPI fold-containing family B member 3 (BPIFB3) as a regulator of autophagy that negatively controls enterovirus replication. Here, we show that in contrast to enteroviruses, BPIFB3 functions as a positive regulator of DENV and ZIKV infection and that its RNA interference-mediated silencing inhibits the formation of viral replication organelles. Mechanistically, we show that depletion of BPIFB3 enhances RETREG1-dependent reticulophagy, leading to enhanced ER turnover and the suppression of viral replication. Consistent with this, the antiviral effects of BPIFB3 depletion can be reversed by RETREG1 silencing, suggesting a specific role for BPIFB3 in regulating ER turnover. These studies define BPIFB3 as a required host factor for both DENV and ZIKV replication and further contribute to our understanding of the requirements for autophagy during flavivirus infection.IMPORTANCE Flaviviruses and other arthropod-transmitted viruses represent a widespread global health problem, with limited treatment options currently available. Thus, a better understanding of the cellular requirements for their infection is needed. Both DENV and ZIKV rely on expansion of the endoplasmic reticulum (ER) and the induction of autophagy to establish productive infections. However, little is known regarding the interplay between the requirements for autophagy initiation during infection and the mechanisms used by these viruses to avoid clearance through the autophagic pathway. Our study highlights the importance of the host factor BPIFB3 in regulating flavivirus replication and further confirms that the RETREG1-dependent reticulophagy pathway is antiviral to both DENV and ZIKV.

Dataset Information

The intramembrane protease SPP impacts morphology of the endoplasmic reticulum by triggering degradation of morphogenic proteins.

Publications

The intramembrane protease SPP impacts morphology of the endoplasmic reticulum by triggering degradation of morphogenic proteins.

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