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Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.

ABSTRACT: Endoplasmic reticulum (ER) is characterized by interconnected tubules and sheets. Neuronal ER adopts specific morphology in axons, dendrites and soma. Here we study mechanisms underlying ER morphogenesis in a C. elegans sensory neuron PVD. In PVD soma and dendrite branch points, ER tubules connect to form networks. ER tubules fill primary dendrites but only extend to some but not all dendritic branches. We find that the Atlastin-1 ortholog, atln-1 is required for neuronal ER morphology. In atln-1 mutants with impaired GTPase activity, ER networks in soma and dendrite branch points are reduced and replaced by tubules, and ER tubules retracted from high-order dendritic branches, causing destabilized microtubule in these branches. The abnormal ER morphology likely causes defects in mitochondria fission at dendritic branch points. Mutant alleles of Atlastin-1 found in Hereditary Spastic Paraplegia (HSP) patients show similar ER phenotypes, suggesting that neuronal ER impairment contributes to HSP disease pathogenesis.

SUBMITTER: Liu X

PROVIDER: S-EPMC6362286 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.

Liu Xianzhuang X Guo Xiangyang X Niu Liling L Li Xixia X Sun Fei F Hu Junjie J Wang Xiangming X Shen Kang K

Nature communications 20190204 1

Endoplasmic reticulum (ER) is characterized by interconnected tubules and sheets. Neuronal ER adopts specific morphology in axons, dendrites and soma. Here we study mechanisms underlying ER morphogenesis in a C. elegans sensory neuron PVD. In PVD soma and dendrite branch points, ER tubules connect to form networks. ER tubules fill primary dendrites but only extend to some but not all dendritic branches. We find that the Atlastin-1 ortholog, atln-1 is required for neuronal ER morphology. In atln- ...[more]

PMID: 30718476

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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

Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.

Publications

Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites.

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