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Research Background However, loss-of-function screening methods cannot screen for a specific protein if the cell line used does not express that protein.
In addition, viruses use multiple host proteins to complete the same process in their replication cycle, and cells will also Multiple host factors are mobilized against the same link in the viral replication cycle, so loss-of-function screening cannot screen all virus-associated factors
.
Discovery of Zika virus inhibitor TMEM120A
TMEM120A and the 2021 Nobel Prize in Physiology or Medicine This study verified whether the suspected ion channel properties of TMEM120A are related to its inhibition of Zika virus infection
.
By what mechanism does TMEM120A inhibit Zika virus infection? Next, the author further explored
.
Research on the mechanism of TMEM120A inhibiting Zika virus infection
Dick, G.
, Kitchen, S.
& Haddow, A.
Zika virus (I).
Isolations and serological specificity.
Transactions of the royal society of tropical medicine and hygiene 46, 509-520 (1952).
2.
Grant, A .
et al.
Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling.
Cell Host Microbe 19, 882-890, doi:10.
1016/j.
chom.
2016.
05.
009 (2016).
3.
Mlakar, J.
et al.
Zika Virus Associated with Microcephaly.
N Engl J Med 374, 951-958, doi:10.
1056/NEJMoa1600651 (2016).
4.
Hoen, B.
et al.
Pregnancy Outcomes after Zika Infection in French Territories in the Americas.
N Engl J Med 378, 985-994, doi:10.
1056/NEJMoa1709481 (2018).
5.
Marceau, CD et al.
Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens.
Nature 535, 159-163, doi:10.
1038/nature18631 ( 2016).
6.
Savidis, G.
et al.
Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics.
Cell Rep 16, 232-246, doi:10.
1016/j.
celrep.
2016.
06.
028 (2016).
7.
Wang, S.
et al.
Integrin alphavbeta5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy.
Cell Rep 30, 969-983 e964, doi:10.
1016/j.
celrep.
2019.
11.
020 (2020).
8.
Beaulieu-Laroche, L.
et al.
TACAN is an ion channel involved in sensing mechanical pain.
Cell 180.
5, 956-967 (2020).
9.
Rong, Y.
et al.
TMEM120A contains a specific coenzyme A-binding site and might not mediate poking-or stretch-induced channel activities in cells.
Elife 10, e71474 (2021).
10.
Niu, Y.
et al.
Analysis of the mechanosensor channel functionality of TACAN.
Elife 10, e71188 (2021).
11.
Xue, J.
et al.
TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase.
Elife 10, e71220 (2021).
12.
Ma, Z.
& Damania, B.
The cGAS-STING Defense Pathway and Its Counteraction by Viruses.
Cell Host Microbe 19, 150-158, doi:10.
1016/j.
chom.
2016.
01.
010 (2016).
In addition, viruses use multiple host proteins to complete the same process in their replication cycle, and cells will also Multiple host factors are mobilized against the same link in the viral replication cycle, so loss-of-function screening cannot screen all virus-associated factors
.
Discovery of Zika virus inhibitor TMEM120A
Figure 1.
Human genome-wide overexpression screening system identified that TMEM120A can inhibit Zika virus infection; a.
The flowchart of the genome-wide overexpression screening system; b.
Scatter plots of the candidate genes obtained from screening; c, d.
Inhibition of Zika virus infection in U87MG cells (c.
Zika virus NS5 RNA level; d.
Zika virus NS1 protein level)
Human genome-wide overexpression screening system identified that TMEM120A can inhibit Zika virus infection; a.
The flowchart of the genome-wide overexpression screening system; b.
Scatter plots of the candidate genes obtained from screening; c, d.
Inhibition of Zika virus infection in U87MG cells (c.
Zika virus NS5 RNA level; d.
Zika virus NS1 protein level)
TMEM120A and the 2021 Nobel Prize in Physiology or Medicine This study verified whether the suspected ion channel properties of TMEM120A are related to its inhibition of Zika virus infection
.
By what mechanism does TMEM120A inhibit Zika virus infection? Next, the author further explored
.
Figure 2.
The mechanically stimulated ion channel activity of TMEM120A (TACAN) is still controversial; a.
In 2020, TMEM120A was first reported to be an ion channel capable of sensing pain stimuli[8]; b.
In 2021, the structure of TMEM120A was reported, and its mechanically stimulated ion channel Permeability questioned [9], Mm: Mus Musculus, Hs: Homo sapiens
The mechanically stimulated ion channel activity of TMEM120A (TACAN) is still controversial; a.
In 2020, TMEM120A was first reported to be an ion channel capable of sensing pain stimuli[8]; b.
In 2021, the structure of TMEM120A was reported, and its mechanically stimulated ion channel Permeability questioned [9], Mm: Mus Musculus, Hs: Homo sapiens
Research on the mechanism of TMEM120A inhibiting Zika virus infection
Figure 3.
TMEM120A directly interacts with STING, promotes STING transport, and activates downstream signaling pathways; a.
TMEM120A localizes to ER (Calnexin is an ER marker); b.
TMEM120A colocalizes with STING; c.
TMEM120A interacts with STING d.
TMEM120A promotes the transport of STING from ER to ERGIC
TMEM120A directly interacts with STING, promotes STING transport, and activates downstream signaling pathways; a.
TMEM120A localizes to ER (Calnexin is an ER marker); b.
TMEM120A colocalizes with STING; c.
TMEM120A interacts with STING d.
TMEM120A promotes the transport of STING from ER to ERGIC
Figure 4.
Schematic diagram of the antiviral mechanism of TMEM120A
references:us"> us"> 1. Schematic diagram of the antiviral mechanism of TMEM120A
Dick, G.
, Kitchen, S.
& Haddow, A.
Zika virus (I).
Isolations and serological specificity.
Transactions of the royal society of tropical medicine and hygiene 46, 509-520 (1952).
2.
Grant, A .
et al.
Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling.
Cell Host Microbe 19, 882-890, doi:10.
1016/j.
chom.
2016.
05.
009 (2016).
3.
Mlakar, J.
et al.
Zika Virus Associated with Microcephaly.
N Engl J Med 374, 951-958, doi:10.
1056/NEJMoa1600651 (2016).
4.
Hoen, B.
et al.
Pregnancy Outcomes after Zika Infection in French Territories in the Americas.
N Engl J Med 378, 985-994, doi:10.
1056/NEJMoa1709481 (2018).
5.
Marceau, CD et al.
Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens.
Nature 535, 159-163, doi:10.
1038/nature18631 ( 2016).
6.
Savidis, G.
et al.
Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics.
Cell Rep 16, 232-246, doi:10.
1016/j.
celrep.
2016.
06.
028 (2016).
7.
Wang, S.
et al.
Integrin alphavbeta5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy.
Cell Rep 30, 969-983 e964, doi:10.
1016/j.
celrep.
2019.
11.
020 (2020).
8.
Beaulieu-Laroche, L.
et al.
TACAN is an ion channel involved in sensing mechanical pain.
Cell 180.
5, 956-967 (2020).
9.
Rong, Y.
et al.
TMEM120A contains a specific coenzyme A-binding site and might not mediate poking-or stretch-induced channel activities in cells.
Elife 10, e71474 (2021).
10.
Niu, Y.
et al.
Analysis of the mechanosensor channel functionality of TACAN.
Elife 10, e71188 (2021).
11.
Xue, J.
et al.
TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase.
Elife 10, e71220 (2021).
12.
Ma, Z.
& Damania, B.
The cGAS-STING Defense Pathway and Its Counteraction by Viruses.
Cell Host Microbe 19, 150-158, doi:10.
1016/j.
chom.
2016.
01.
010 (2016).
