Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition

Sim, Ju‐Ri; Shin, Dong Hoon; Park, Pil-Gu; Park, Sohyeon; Bae, Joon‐Yong; Lee, Youngchae; Kang, Dha-Yei; Kim, Ye Jin; Aum, Sowon; Noh, Shin Hye; Hwang, Su Jin; Cha, Hye‐Ran; Kim, Cheong Bi; Ko, Si Hwan; Park, Sunghoon; Jeon, Dongkyu; Jo, Sungwoo; Lee, Gee Eun; Kim, Jeonghun; Moon, Yong; Kim, Jae-Ouk; Nam, Jae Sung; Kim, Chang Hoon; Moon, Sungmin; Chung, Youn Wook; Park, Man‐Seong; Ryu, Ji-Hwan; Namkung, W.; Lee, Jae Myun; Lee, Min Goo

doi:10.1016/j.celrep.2022.111117

Cited by 13 publications

(16 citation statements)

References 46 publications

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“…This study mechanistically delineates that the SARS-CoV-2 S-protein increases Ca 2+ oscillations in the cells thereby enhancing the activity of plasma membrane TMEM16 channel [29] . Recently, Sim et al corroborated a critical role of TMEM16F in SARS-CoV-2 fusion with host cell plasma membrane and subsequent entry into host cells [30] . The authors demonstrated that SARS-CoV-2 S-protein induces rise in cytosolic Ca 2+ which in turn leads to TMEM16F mediated plasma membrane exposure of phosphatidylserine in ACE2 expressing cells.…”

Section: Sars-cov-2 Utilizes Host Ca 2+ Signaling ...mentioning

confidence: 93%

“…Importantly, the authors carried out a high throughput screening of 56,000 small molecules for identifying the TMEM16F inhibitors and identified three independent structural classes of drugs that could inhibit TMEM16F. Notably, a highly specific and potent inhibitor of TMEM16F (A6-001) was identified, which abrogated both SARS-CoV-2 stimulated phosphatidylserine exposure and SARS-CoV-2 replication in a variety of host cells [30] . Taken together, these studies establish a crucial role for TMEM16F in SARS-CoV-2 entry into host cells.…”

Section: Sars-cov-2 Utilizes Host Ca 2+ Signaling ...mentioning

confidence: 99%

“…IP 3 acts as a second messenger that activates Ca 2+ release into the cytoplasm from the ER stores upon binding to IP 3 R. Other molecules shown to be effective in prevention of syncytia formation belongs to the tricyclic antidepressants and the L-type Ca 2+ channel blockers that inhibit the voltage-dependent L-type calcium channels [29] . Non-canonical channels such TMEM16F and Panx1 are also shown to modulate Ca 2+ signaling upon SARS-CoV-2 infection [29] , [30] , [31] , [32] . The tussle between the host and the virus for modulating Ca 2+ signaling is critical in mounting infection and pathogenesis.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis

2022

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Section: Sars-cov-2 Utilizes Host Ca 2+ Signaling ...mentioning

confidence: 93%

Section: Sars-cov-2 Utilizes Host Ca 2+ Signaling ...mentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

See 1 more Smart Citation

Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis

2022

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“… 70 , 71 However, either endogenous ACE2 in Vero E6 cells or the transiently expressed ACE2 in CHO cells is not enriched in lipid rafts. 72 , 73 The controversial results might be caused by different experimental methods. How and which receptors are recruited to the lipid rafts requires further investigation.…”

Section: Introductionmentioning

confidence: 99%

Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection

Chen

et al. 2023

Sig Transduct Target Ther

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The coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden to our society. Most patients infected by SARS-CoV-2 are asymptomatic or have mild symptoms. Although only a small proportion of patients progressed to severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, and cardiovascular disorders, severe COVID-19 is accompanied by high mortality rates with near 7 million deaths. Nowadays, effective therapeutic patterns for severe COVID-19 are still lacking. It has been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate host metabolism to avoid immunity, facilitate their own replication, or to initiate pathological response. Targeting the interaction between SARS-CoV-2 and host metabolism holds promise for developing therapeutic strategies. In this review, we summarize and discuss recent studies dedicated to uncovering the role of host metabolism during the life cycle of SARS-CoV-2 in aspects of entry, replication, assembly, and pathogenesis with an emphasis on glucose metabolism and lipid metabolism. Microbiota and long COVID-19 are also discussed. Ultimately, we recapitulate metabolism-modulating drugs repurposed for COVID-19 including statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, and metformin.

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“…It is an intriguing open question regarding the origins of the recruited membrane for cell surface expansion and its proteomic composition, as well as the full physiological ramifications of this phenomenon. In addition to regulating cellular surface area, TMEM16F (Transmembrane Protein Family 16 Member F, encoded by the ANO6 gene) has been shown to be a critical factor for phospholipid scrambling (Yang et al, 2012), extracellular vesicle release (Fujii et al, 2015), plasma membrane wound repair (Wu et al, 2020), syncytia formation (cell-cell fusion) for placenta formation during embryogenesis (Zhang et al, 2020) and as induced by SARS-CoV2 infection (Braga et al, 2021), as well as host cell entry of various pathogens including HIV (Zaitseva et al, 2017), Ebola virus (Acciani et al, 2021), and SARS-CoV2 (Sim et al, 2022). Relating to its role in extracellular vesicle release, TMEM16F is also the causative factor in Scott syndrome, a rare congenital bleeding disorder (Suzuki et al, 2010), where platelets of individuals with homozygous loss-of-function mutations fail to execute non-apoptotic plasma membrane phosphatidylserine scrambling necessary for the release of coagulating factor-containing extracellular vesicles (Ahmad et al, 1989; Bevers et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

SLAPSHOT reveals rapid dynamics of extracellularly exposed proteome in response to calcium-activated plasma membrane phospholipid scrambling

Tuomivaara

Teo

Jan

et al. 2023

Preprint

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To facilitate our understanding of the often rapid and nuanced dynamics of extracellularly exposed proteomes during signaling events, it is important to devise robust workflows affording fast time resolution without biases and confounding factors. Here, we present Surface-exposed protein Labeling using PeroxidaSe, H2O2, and Tyramide-derivative (SLAPSHOT), to label extracellularly exposed proteins in a rapid, sensitive, and specific manner, while preserving cellular integrity. This experimentally simple and flexible method utilizes recombinant soluble APEX2 peroxidase that is applied to cells, thus circumventing biological perturbations, tedious engineering of tools and cells, and labeling biases. APEX2 neither requires metal cations for activity nor contains disulfide bonds, conferring versatility for a wide spectrum of experimental setups. We applied SLAPSHOT followed by quantitative mass spectrometry-based proteomics analysis to examine the immediate and extensive cell surface expansion and ensuing restorative membrane shedding upon the activation of Scott syndrome-linked TMEM16F, a ubiquitously expressed calcium-dependent phospholipid scramblase and ion channel. Time-course data ranging from one to thirty minutes of calcium stimulation using wild-type and TMEM16F deficient cells revealed intricate co-regulation of known protein families, including those in the integrin and ICAM families. Crucially, we identified proteins that are known to reside in intracellular organelles, including ER, as occupants of the freshly deposited membrane, and mitovesicles as an abundant component and contributor to the extracellularly exposed proteome. Our study not only provides the first accounts of the immediate consequences of calcium signaling on the extracellularly exposed proteome, but also presents a blueprint for the application of SLAPSHOT as a general approach for monitoring extracellularly exposed protein dynamics.

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Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition

Cited by 13 publications

References 46 publications

Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis

Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis

Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection

SLAPSHOT reveals rapid dynamics of extracellularly exposed proteome in response to calcium-activated plasma membrane phospholipid scrambling

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