TMEM41B Is a Pan-flavivirus Host Factor

Hoffmann, Hans-Heinrich; Schneider, William M.; Rozen-Gagnon, Kathryn; Miles, Linde A.; Schuster, Felix Paul; Razooky, Brandon S.; Jacobson, Eliana; Wu, Xianfang; Yi, Soon; Rudin, Charles M.; MacDonald, Margaret R.; McMullan, Laura K.; Poirier, John T.; Rice, Charles M.

doi:10.1016/j.cell.2020.12.005

Cited by 144 publications

(181 citation statements)

References 89 publications

(78 reference statements)

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“…Recent studies using genome-wide CRISPR/cas9 knockout screens with SARS-CoV-2 infection have identified a plethora of host factors important for productive infection by SARS-CoV-2 (Daniloski et al, 2021; Hoffmann et al, 2021; Schneider et al, 2021; Wang et al, 2021; Wei et al, 2021). The list of necessary host factors required for SARS-CoV-2 propagation varied widely among the different screens, likely due to different cell types and infection conditions used for each screen.…”

Section: Resultsmentioning

confidence: 99%

ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling

Ramaiah

García

et al. 2021

Preprint

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ORAI1 and STIM1 are the critical mediators of store-operated Ca2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca2+ signaling, STIM1 is also involved in regulation of a cytosolic nucleic acid sensing pathway. Using ORAI1 and STIM1 knockout cells, we examined their contribution to the host response to SARS-CoV-2 infection. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection due to enhanced type I interferon response. On the contrary, ORAI1 knockout cells showed high susceptibility to SARS-CoV-2 infection as judged by increased expression of viral proteins and a high viral load. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca2+ concentration and severe impairment in tonic interferon signaling. Transcriptome analysis showed downregulation of multiple cellular defense mechanisms, including antiviral signaling pathways in ORAI1 knockout cells, which are likely due to reduced expression of the Ca2+-dependent transcription factors of the activator protein 1 (AP-1) family and MEF2C. Our results identify a novel role of ORAI1-mediated Ca2+ signaling in regulating the baseline type I interferon level, which is a determinant of host resistance to SARS-CoV-2 infection.

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Section: Resultsmentioning

confidence: 99%

ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling

Ramaiah

García

et al. 2021

Preprint

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“…Despite being implicated for multiple flaviviruses, until very recently, there had been little follow-up or characterization. In January 2021, another study using genome-wide screening approaches for ZIKV and yellow fever virus host factors also identified TMEM41B as an essential host factor; in fact, it appears that TMEM41B is broadly required for most, if not all, flaviviruses [ 31 ]. Mechanistic studies with flaviviruses have revealed that TMEM41B physically interacts with the viral proteins NS4A and/or NS4B and is strongly relocalized to viral replication complexes [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

TMEM41B is a host factor required for the replication of diverse coronaviruses including SARS-CoV-2

et al. 2021

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Antiviral therapeutics are a front-line defense against virally induced diseases. Because viruses frequently mutate to escape direct inhibition of viral proteins, there is interest in targeting the host proteins that the virus must co-opt to complete its replication cycle. However, a detailed understanding of the interactions between the virus and the host cell is necessary in order to facilitate development of host-directed therapeutics. As a first step, we performed a genome-wide loss of function screen using the alphacoronavirus HCoV-229E to better define the interactions between coronaviruses and host-factors. We report the identification and validation of an ER-resident host protein, TMEM41B, as an essential host factor for not only HCoV-229E but also genetically distinct coronaviruses including the pandemic beta-coronavirus SARS-CoV-2. We show that the protein is required at an early, but post-receptor engagement, stage of the viral lifecycle. Further, mechanistic studies revealed that although the protein was not enriched at replication complexes, it likely contributes to viral replication complex formation via mobilization of cholesterol and other lipids to facilitate host membrane expansion and curvature. Continued study of TMEM41B and the development of approaches to prevent its function may lead to broad spectrum anti-coronavirus therapeutics.

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“…4d), suggesting a role of TMEM41B in a post-entry step. A recent study also suggested a post-entry role of TMEM41B in flavivirus replication complex formation 30 . Together, these data identify the autophagy protein TMEM41B as an indispensable host factor for HCoV-229E.…”

Section: Pi3k Type 3 Is a Druggable Common Anti-coronavirus Targetmentioning

confidence: 96%

Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2

et al. 2021

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he COVID-19 pandemic, caused by SARS-CoV-2, has resulted in a worldwide health crisis 1 and few effective drugs are available to treat patients with COVID-19. Although remdesivir initially seemed promising for severe cases 2 , the World Health Organization's Solidarity trial showed that it has no definite impact on mortality 3. Dexamethasone can reduce mortality by a third among critically ill patients with COVID-19, by suppressing the hyperactive immune response 4. However, as treatment benefits severe cases only to a limited extent, efficient and safe therapeutics are urgently required while awaiting the worldwide implementation of vaccines. Coronaviruses cause respiratory and intestinal infections in a broad range of mammals and birds. Seven human coronaviruses (HCoVs) are known, which probably all emerged as zoonoses from bats, mice or domestic animals 5. The four so-called 'common cold HCoVs'-229E, NL63, OC43 and HKU1-cause mild upper respiratory tract illnesses 6. In contrast, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV) and the recently emerged SARS-CoV-2 are highly pathogenic and cause severe, potentially lethal respiratory infections. As numerous coronaviruses reside in animal reservoirs and interspecies transmission frequently occurs 5,7,8 , there is a constant risk of new pathogenic coronaviruses spreading into the human population, as exemplified by the recent SARS-CoV-2 pandemic. Nevertheless, our options to prevent or treat coronavirus infections remain limited. Hence, the development of broad-spectrum anti-coronavirus drugs could help not only to address the current high medical need, but also to quickly contain zoonotic events in the future. Common host factors essential for replication of multiple coronaviruses represent attractive targets for broad-spectrum antiviral drugs. To develop such drugs, it is crucial to understand which host factors coronaviruses require to infect a cell, because each step of the coronavirus replication cycle (receptor binding, endocytosis, fusion, viral protein translation, genome replication, virion assembly and release) may serve as a target for intervention. Although the entry step of coronaviruses has been relatively well characterized, the host-virus interplay in later steps of the viral life cycle remains largely elusive. For SARS-CoV-2, previous studies have shown that the protein angiotensin-converting enzyme 2 (ACE2) can serve as a receptor in Vero E6 cells 9 or in human cells overexpressing ACE2 (refs. 10-12). In addition, it was shown that the SARS-CoV-2 spike (S) can be primed for fusion by cellular proteases such as furin, transmembrane serine protease 2 (TMPRSS2) or cathepsin B or L, depending on the target cell type 10,13. In the present study, we performed a series of genome-wide CRISPR (clustered regularly interspaced short palindromic repeats)-based genetic screens to identify host factors required for SARS-CoV-2 and HCoV-229E infection. We identified phosphoinositide 3-kinase (PI3K) type 3 as a common host factor for SARS-CoV-2,...

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TMEM41B Is a Pan-flavivirus Host Factor

Cited by 144 publications

References 89 publications

ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling

ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling

TMEM41B is a host factor required for the replication of diverse coronaviruses including SARS-CoV-2

Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2

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