Atlastin-mediated membrane tethering is critical for cargo mobility and exit from the endoplasmic reticulum

Niu, Liling; Ma, Tianji; Yang, F.; Yan, Bing; Tang, Xiao Song; Yin, Haidi; Wu, Qian; Huang, Yan; Yao, Zhongping; Wang, Jifeng; Guo, Yusong; Hu, Junjie

doi:10.1073/pnas.1908409116

Cited by 53 publications

(54 citation statements)

References 66 publications

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“…Future work will help understanding the functional consequences of ATL-NS protein interaction. Furthermore, a recent study shows a role for ATL3 in ER export of cargo proteins into COPII vesicles (53). It would be of interest to determine whether ATL play also a role the transport or release of viral particles.…”

Section: Fig 10 Atl3 Colocalizes and Interacts With Zikv Ns Proteinsmentioning

confidence: 99%

Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication

Monel

Rajah

Hafirassou

et al. 2019

J Virol

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The endoplasmic reticulum (ER) is the site for Zika virus (ZIKV) replication and is central to the cytopathic effects observed in infected cells. ZIKV induces the formation of ER-derived large cytoplasmic vacuoles followed by “implosive” cell death. Little is known about the nature of the ER factors that regulate flavivirus replication. Atlastins (ATL1, -2, and -3) are dynamin-related GTPases that control the structure and the dynamics of the ER membrane. We show here that ZIKV replication is significantly decreased in the absence of ATL proteins. The appearance of infected cells is delayed, the levels of intracellular viral proteins and released virus are reduced, and the cytopathic effects are strongly impaired. We further show that ATL3 is recruited to viral replication sites and interacts with the nonstructural viral proteins NS2A and NS2B3. Thus, proteins that shape and maintain the ER tubular network ensure efficient ZIKV replication. IMPORTANCE Zika virus (ZIKV) is an emerging virus associated with Guillain-Barré syndrome, and fetal microcephaly as well as other neurological complications. There is no vaccine or specific antiviral treatment against ZIKV. We found that endoplasmic reticulum (ER)-shaping atlastin proteins (ATL1, -2, and -3), which induce ER membrane fusion, facilitate ZIKV replication. We show that ATL3 is recruited to the viral replication site and colocalize with the viral proteins NS2A and NS2B3. The results provide insights into host factors used by ZIKV to enhance its replication.

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Section: Fig 10 Atl3 Colocalizes and Interacts With Zikv Ns Proteinsmentioning

confidence: 99%

Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication

Monel

Rajah

Hafirassou

et al. 2019

J Virol

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“…An in vitro vesicle formation assay to reconstitute packaging of cargo proteins into vesicles from mammalian cells has been well-established (Kim et al, 2007;Ma et al, 2018;Merte et al, 2010;Niu et al, 2019). We sought to perform this assay in HEK293T cells on a large scale and then perform proteomic analysis on the isolated vesicles.…”

Section: An In Vitro Reconstituted Vesicle Formation Assay For Proteomentioning

confidence: 99%

“…Mass spectrometry and data analysis was performed as described (Niu et al, 2019). Briefly, LC separation was performed using an Acclaim PepMap RSLC C18 capillary column (75 μm × 25 cm; 2 μm particles, 100 Å) (Thermo fisher Scientific, San Jose, CA).…”

Section: Mass Spectrometry and Data Analysismentioning

confidence: 99%

Anin vitrovesicle formation assay to analyze protein sorting in the secretory transport pathway

Huang

Yin

Tang

et al. 2020

Preprint

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The fidelity of protein transport in the secretory transport pathway relies on the accurate sorting of proteins to their correct destination. To deepen our understanding of the underlying molecular mechanisms, it is important to develop a robust approach to systematically reveal cargo proteins that depend on a specific cargo sorting machinery to be efficiently packaged into vesicles. Here, we used an in vitro assay that reconstitutes packaging of human cargo proteins into vesicles to quantify cargo capture. Quantitative mass spectrometry analyses of the isolated vesicles revealed novel cytosolic proteins that are associated with vesicle membranes in a GTP-dependent manner or that interact with GTP-bound Sar1A on vesicle membranes. Functional analysis indicates that two of them, FAM84B and PRRC1, regulate anterograde trafficking. Comparing control cells with cells depleted of the cargo receptors, SURF4 or ERGIC53, we revealed specific clients of each of these two export adaptors.Moreover, our results indicate that vesicles enriched with a specific cargo protein contain specific transmembrane cargo and SNARE proteins. A SNARE protein, Vti1B, is identified to be in vesicles enriched with a planar cell polarity protein, Frizzled6, and promotes vesicular release of Frizzled6. Our results indicate that the vesicle formation assay in combination with quantitative mass spectrometric analysis is a robust and powerful tool to reveal novel cytosolic and transmembrane proteins that regulate trafficking of a specific cargo protein.

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“…To date, however, this ability to promote fusion has been demonstrated exclusively for invertebrate atlastins (Orso et al, 2009;Anwar et al, 2012;Zhang et al, 2013;Wu et al, 2014). An involvement of atlastin in controlling Golgi morphology (Namekawa et al, 2007;Rismanchi et al, 2008;Chen et al, 2011;Behrendt et al, 2019) as well as in COPII formation (Niu et al, 2019) has also been proposed. However, the former was based exclusively on overexpression experiments and the latter has been identified using a very specific mutation (R48A/R77A) capable of uncoupling fusion and tethering (Pendin et al, 2011;Niu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

In vivo Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in Drosophila

et al. 2020

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The endoplasmic reticulum (ER) is a highly dynamic network whose shape is thought to be actively regulated by membrane resident proteins. Mutation of several such morphology regulators cause the neurological disorder Hereditary Sp astic Paraplegia (HSP), suggesting a critical role of ER shape maintenance in neuronal activity and function. Human Atlastin-1 mutations are responsible for SPG3A, the earliest onset and one of the more severe forms of dominant HSP. Atlastin has been initially identified in Drosophila as the GTPase responsible for the homotypic fusion of ER membrane. The majority of SPG3A-linked Atlastin-1 mutations map to the GTPase domain, potentially interfering with atlastin GTPase activity, and to the three-helix-bundle (3HB) domain, a region critical for homo-oligomerization. Here we have examined the in vivo effects of four pathogenetic missense mutations (two mapping to the GTPase domain and two to the 3HB domain) using two complementary approaches: CRISPR/Cas9 editing to introduce such variants in the endogenous atlastin gene and transgenesis to generate lines overexpressing atlastin carrying the same pathogenic variants. We found that all pathological mutations examined reduce atlastin activity in vivo although to different degrees of severity. Moreover, overexpression of the pathogenic variants in a wild type atlastin background does not give rise to the loss of function phenotypes expected for dominant negative mutations. These results indicate that the four pathological mutations investigated act through a loss of function mechanism.

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Atlastin-mediated membrane tethering is critical for cargo mobility and exit from the endoplasmic reticulum

Cited by 53 publications

References 66 publications

Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication

Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication

Anin vitrovesicle formation assay to analyze protein sorting in the secretory transport pathway

In vivo Analysis of CRISPR/Cas9 Induced Atlastin Pathological Mutations in Drosophila

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