PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding

Soares, Alberto; Ferreira, Andreia; Mariën, Jonas; Delay, Charlotte; Lee, Edward; Trojanowski, John Q.; Moechars, Dieder; Annaert, Wim; Muynck, Louis De

doi:10.1016/j.jbc.2021.100636

“…Prevailing models for the cellular location of TMPRSS2-activated SARS-CoV-2 entry favor fusion at the cell surface rather than from endosomal compartments because TMPRSS2 activity is pH independent. Ebola virus or SARS-CoV-2 accumulate in EEA1-containing early endosomes ( 3 , 20 ), a behavior consistent with the disruption of endolysosomal traffic that occurs when PIKfyve kinase activity is inhibited by genetic or pharmacological means ( 21 , 40 , 42 ). It is therefore possible that changes in the endosomal milieu, combined with the redirection of SARS-CoV-2 and/or TMPRSS2 traffic in the presence of apilimod, might make infection more dependent on TMPRSS2 pharmacological inactivation than in its absence.…”

Section: Resultsmentioning

confidence: 78%

Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease

Kreutzberger

¹

,

Sanyal

²

,

Ojha

³

et al. 2021

J Virol

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Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike S protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic, and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ∼5-10-fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both, a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2 virus. The substantial ∼5-fold or more decrease of half maximal effective concentrations (EC 50 values) suggests a plausible treatment strategy based on the combined use of these inhibitors. IMPORTANCE Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the coronavirus disease 2019 (COVID-2019) global pandemic. There are ongoing efforts to uncover effective antiviral agents that could mitigate the severity of the disease by controlling the ensuing viral replication. Promising candidates include small molecules that inhibit the enzymatic activities of host proteins, thus preventing SARS-CoV-2 entry and infection. They include Apilimod, an inhibitor of PIKfyve kinase and camostat mesylate and nafamostat mesylate, inhibitors of TMPRSS2 protease. Our research is significant for having uncovered an unexpected synergism in the effective inhibitory activity of apilimod used together with camostat mesylate or with nafamostat mesylate.

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“…Interestingly, formation of endolysosomes can also be blocked by interfering with PIKfyve (1-phosphatidylinositol 3-phosphate 5-kinase). Pharmacological inhibition of PIKfyve resulted in increased accumulation of internalized tau fibrils and α-synuclein fibrils in early endosomes before being sorted to lysosomes, thereby inhibiting the escape of seeds from late endocytic compartments [98,99]. Furthermore, inhibition of other kinases such as p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C (PKC) also appears to regulate endolysosomal permeabilization [100].…”

Section: Accepted Articlementioning

confidence: 99%

Exosomal and vesicle‐free tau seeds—propagation and convergence in endolysosomal permeabilization

Polanco

¹

,

Götz

²

2021

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transgenic mice expressing mutant tau P301S driven by the mouse prion protein promoter; RAB35, Ras-related protein Rab-35 small GTPase; RAB5, Ras-related protein Rab-5 small GTPase; RAB7, Ras-related protein Rab-7 small GTPase; RAB8A, Ras-related protein Rab-8A small GTPase; SOD1, superoxide dismutase [Cu-Zn]; TDP 43, TAR DNA-binding protein 43; TIA1, nucleolysin TIA-1 isoform p40; TRIM16, tripartite motif-containing protein 16; TSG101, tumor susceptibility gene 101 protein; VPS4, vacuolar protein sorting-associated protein 4A.

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“…Prevailing models for the cellular location of TMPRSS2-activated SARS-CoV-2 entry favor fusion at the cell surface rather than from endosomal compartments, because TMPRSS2 activity is pH independent. Ebola or SARS-CoV-2 viruses accumulate in EEA1 containing early endosomes (3, 20), a behavior consistent with the disruption of endolysosomal traffic that occurs when PIKfyve kinase activity is inhibited by genetic or pharmacological means (21, 40, 42). It is therefore possible that changes in the endosomal milieu, combined with redirection of SARS-CoV-2 and/or TMPRSS2 traffic in the presence of apilimod, might make infection more dependent on TMPRSS2 pharmacological inactivation than in its absence.…”

Section: Resultsmentioning

confidence: 79%

Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease

Kreutzberger

¹

,

Sanyal

²

,

Ojha

³

et al. 2021

Preprint

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Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike S protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic, and through an ill-defined mechanism prevents in vitro infection through late endosomes mediated by cathepsin. Similarly, inhibition of TMPRSS2 protease activity by camostat mesylate or nafamostat mesylate prevents infection mediated by the TMPRSS2-dependent and cathepsin-independent pathway. Here, we combined the use of apilimod with camostat mesylate or nafamostat mesylate and found an unexpected ~5-10 fold increase in their effectiveness to prevent SARS-CoV-2 infection in different cell types. Comparable synergism was observed using both, a chimeric vesicular stomatitis virus (VSV) containing S of SARS-CoV-2 (VSV-SARS-CoV-2) and SARS-CoV-2 virus. The substantial ~5 fold or more decrease of half maximal effective concentrations (EC50 values) suggests a plausible treatment strategy based on the combined use of these inhibitors.

show abstract

PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding

Cited by 27 publications

References 78 publications

Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease

Synergistic Block of SARS-CoV-2 Infection by Combined Drug Inhibition of the Host Entry Factors PIKfyve Kinase and TMPRSS2 Protease

Exosomal and vesicle‐free tau seeds—propagation and convergence in endolysosomal permeabilization

Synergistic block of SARS-CoV-2 infection by combined drug inhibition of the host entry factors PIKfyve kinase and TMPRSS2 protease

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