TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

Kishimoto, Mai; Uemura, Kentaro; Sanaki, Takao; Sato, Akihiko; Hall, William W.; Kariwa, Hiroaki; Orba, Yasuko; Sawa, Hirofumi; Sasaki, Michihito

doi:10.3390/v13030384

Cited by 56 publications

(44 citation statements)

References 43 publications

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“…TMPRSS2 activated the S proteins of all four CoVs, in keeping with published data [31,[59][60][61][62][63][64][65]. Intriguingly, TMPRSS13 enhanced entry driven by the S proteins of the highly virulent SARS-CoV, SARS-CoV-2 and MERS-CoV (in line with other reports [33,34,58]), but not the common cold virus HCoV-229E. MERS-S and 229E-S were both activated by HAT, as reported earlier [63,66], with roughly the same efficiency as TMPRSS2.…”

Section: Among All 18 Ttsps Tmprss2 and Tmprss13 Are The Best Activators Of Sars-2-ssupporting

confidence: 90%

“…HAT proved effective on 229E-S and MERS-S, however it was less active on SARS-S and SARS-2-S, as reported earlier [33,34,58,63]. We did not see the recently reported activation of SARS-2-S by DESC1 [33,34] and TMPRSS11F [33], which belong to the same subfamily as HAT. This suggests that the level of TTSP activation depends on assay conditions, in particular the level of protease that is generated by plasmid transfection.…”

Section: Plos Pathogenscontrasting

confidence: 42%

“…This suggests that the level of TTSP activation depends on assay conditions, in particular the level of protease that is generated by plasmid transfection. Still, the most intriguing result regards TMPRSS13, which we and others [33,34,58] established as a second potent activator of SARS-S, SARS-2-S and MERS-S, but not 229E-S. Since this protease prefers cleavage sites with a second basic residue at positions P2 or P4 [70], it plausibly recognizes the S2 0 site at the KR motif of SARS-S and SARS-2-S, and the RSAR motif of MERS-S.…”

Section: Plos Pathogensmentioning

confidence: 74%

“…The Type II Transmembrane Serine Protease (TTSP) family, to which TMPRSS2 belongs, contains in total 18 proteases, many of which are expressed in human airways [13]. Two recent analyses with a subset of TTSPs identified TMPRSS13 as a second prominent activator of the SARS-CoV-2 S protein (subsequently referred to as SARS-2-S) [33,34].…”

Section: Introductionmentioning

confidence: 99%

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The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways

et al. 2021

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The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways. Pseudoviruses bearing the SARS-CoV-2 spike (SARS-2-S) were more infectious when produced at 33°C instead of 37°C, a property shared with the S protein of HCoV-229E, a common cold coronavirus. In contrast, the S proteins of SARS-CoV and MERS-CoV favored 37°C, in accordance with virus preference for the lower airways. Next, SARS-2-S-driven entry was efficiently activated by not only TMPRSS2, but also the TMPRSS13 protease, thus broadening the cell tropism of SARS-CoV-2. Both proteases proved relevant in the context of authentic virus replication. TMPRSS13 appeared an effective spike activator for the virulent coronaviruses but not the low pathogenic HCoV-229E virus. Activation of SARS-2-S by these surface proteases requires processing of the S1/S2 cleavage loop, in which both the furin recognition motif and extended loop length proved critical. Conversely, entry of loop deletion mutants is significantly increased in cathepsin-rich cells. Finally, we demonstrate that the D614G mutation increases SARS-CoV-2 stability, particularly at 37°C, and, enhances its use of the cathepsin L pathway. This indicates a link between S protein stability and usage of this alternative route for virus entry. Since these spike properties may promote virus spread, they potentially explain why the spike-G614 variant has replaced the early D614 variant to become globally predominant. Collectively, our findings reveal adaptive mechanisms whereby the coronavirus spike protein is adjusted to match the temperature and protease conditions of the airways, to enhance virus transmission and pathology.

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Section: Among All 18 Ttsps Tmprss2 and Tmprss13 Are The Best Activators Of Sars-2-ssupporting

confidence: 90%

Section: Plos Pathogenscontrasting

confidence: 42%

Section: Plos Pathogensmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways

et al. 2021

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“…Also, we found overexpression of other genes such as ACE2, STAT1 44 , and TMPRSS13 48 (Figure 5A and Table S8) that are elevated in critical COVID-19 disease.…”

Section: The N Mutant (R203k/g204r) Induces Overexpression Of Interferon Related Genes In Transfected Host Cellsmentioning

confidence: 85%

Saudi Arabian SARS-CoV-2 genomes implicate a mutant Nucleocapsid protein in modulating host interactions and increased viral load in COVID-19 patients

Mourier

Shuaib

Hala

et al. 2021

Preprint

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Monitoring SARS-CoV-2 spread and evolution through genome sequencing is essential in handling the COVID-19 pandemic. The availability of patient hospital records is crucial for linking the genomic sequence information to virus function during the course of infections. Here, we sequenced 892 SARS-CoV-2 genomes collected from patients in Saudi Arabia from March to August 2020. From the assembled sequences, we estimate the SARS-CoV-2 effective population size and infection rate and outline the epidemiological dynamics of import and transmission events during this period in Saudi Arabia. We show that two consecutive mutations (R203K/G204R) in the SARS-CoV-2 nucleocapsid (N) protein are associated with higher viral loads in COVID-19 patients. Our comparative biochemical analysis reveals that the mutant N protein displays enhanced viral RNA binding and differential interaction with key host proteins. We found hyper-phosphorylation of the adjacent serine site (S206) in the mutant N protein by mass-spectrometry analysis. Furthermore, analysis of the host cell transcriptome suggests that the mutant N protein results in dysregulated interferon response genes. We provide crucial information in linking the R203K/G204R mutations in the N protein as a major modulator of host-virus interactions and increased viral load and underline the potential of the nucleocapsid protein as a drug target during infection.

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Meta‐analysis of age‐related cognitive decline reveals a novel locus for the attention domain and implicates a COVID‐19‐related gene for global cognitive function

Acharya

Fan

Snitz

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONCognitive abilities have substantial heritability throughout life, as shown by twin‐ and population‐based studies. However, there is limited understanding of the genetic factors related to cognitive decline in aging across neurocognitive domains.METHODSWe conducted a meta‐analysis on 3045 individuals aged ≥65, derived from three population‐based cohorts, to identify genetic variants associated with the decline of five neurocognitive domains (attention, memory, executive function, language, visuospatial function) and global cognitive decline. We also conducted gene‐based and functional bioinformatics analyses.RESULTSApolipoprotein E (APOE)4 was significantly associated with decline of memory (p = 5.58E‐09) and global cognitive function (p = 1.84E‐08). We identified a novel association with attention decline on chromosome 9, rs6559700 (p = 2.69E‐08), near RASEF. Gene‐based analysis also identified a novel gene, TMPRSS11D, involved in the activation of SARS‐CoV‐2, to be associated with the decline in global cognitive function (p = 4.28E‐07).DISCUSSIONDomain‐specific genetic studies can aid in the identification of novel genes and pathways associated with decline across neurocognitive domains.Highlights rs6559700 was associated with decline of attention. APOE4 was associated with decline of memory and global cognitive decline. TMPRSS11D, a gene involved in the activation of SARS‐CoV‐2, was implicated in global cognitive decline. Cognitive domain abilities had both unique and shared molecular pathways across the domains.

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TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein

Cited by 56 publications

References 43 publications

The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways

The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways

Saudi Arabian SARS-CoV-2 genomes implicate a mutant Nucleocapsid protein in modulating host interactions and increased viral load in COVID-19 patients

Meta‐analysis of age‐related cognitive decline reveals a novel locus for the attention domain and implicates a COVID‐19‐related gene for global cognitive function

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