tetano
Editor, Senior Moderator
Sci Adv
. 2022 Dec 23;8(51):eade5085.
doi: 10.1126/sciadv.ade5085. Epub 2022 Dec 23.
The D614G mutation redirects SARS-CoV-2 spike to lysosomes and suppresses deleterious traits of the furin cleavage site insertion mutation
Chenxu Guo 1 , Shang-Jui Tsai 1 , Yiwei Ai 1 , Maggie Li 2 , Eduardo Anaya 2 , Andrew Pekosz 2 , Andrea Cox 3 , Stephen J Gould 1
Affiliations
PMID: 36563151 DOI: 10.1126/sciadv.ade5085
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) egress occurs by lysosomal exocytosis. We show that the Spike D614G mutation enhances Spike trafficking to lysosomes, drives Spike-mediated reprogramming of lysosomes, and reduces cell surface Spike expression by ~3-fold. D614G is not a human-specific adaptation. Rather, it is an adaptation to the earlier furin cleavage site insertion (FCSI) mutation that occurred at the genesis of SARS-CoV-2. While advantageous to the virus, furin cleavage of spike has deleterious effects on spike structure and function, inhibiting its trafficking to lysosomes and impairing its infectivity by the transmembrane serine protease 2(TMPRSS2)-independent, endolysosomal pathway. D614G restores spike trafficking to lysosomes and enhances the earliest events in SARS-CoV-2 infectivity, while spike mutations that restore SARS-CoV-2's TMPRSS2-independent infectivity restore spike's trafficking to lysosomes. Together, these and other results show that D614G is an intragenic suppressor of deleterious traits linked to the FCSI and lend additional support to the endolysosomal model of SARS-CoV-2 egress and entry.
Chenxu Guo[SUP] 1 [/SUP], Shang-Jui Tsai[SUP] 1 [/SUP], Yiwei Ai[SUP] 1 [/SUP], Maggie Li[SUP] 2 [/SUP], Eduardo Anaya[SUP] 2 [/SUP], Andrew Pekosz[SUP] 2 [/SUP], Andrea Cox[SUP] 3 [/SUP], Stephen J Gould[SUP] 1 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) egress occurs by lysosomal exocytosis. We show that the Spike D614G mutation enhances Spike trafficking to lysosomes, drives Spike-mediated reprogramming of lysosomes, and reduces cell surface Spike expression by ~3-fold. D614G is not a human-specific adaptation. Rather, it is an adaptation to the earlier furin cleavage site insertion (FCSI) mutation that occurred at the genesis of SARS-CoV-2. While advantageous to the virus, furin cleavage of spike has deleterious effects on spike structure and function, inhibiting its trafficking to lysosomes and impairing its infectivity by the transmembrane serine protease 2(TMPRSS2)-independent, endolysosomal pathway. D614G restores spike trafficking to lysosomes and enhances the earliest events in SARS-CoV-2 infectivity, while spike mutations that restore SARS-CoV-2's TMPRSS2-independent infectivity restore spike's trafficking to lysosomes. Together, these and other results show that D614G is an intragenic suppressor of deleterious traits linked to the FCSI and lend additional support to the endolysosomal model of SARS-CoV-2 egress and entry.
. 2022 Dec 23;8(51):eade5085.
doi: 10.1126/sciadv.ade5085. Epub 2022 Dec 23.
The D614G mutation redirects SARS-CoV-2 spike to lysosomes and suppresses deleterious traits of the furin cleavage site insertion mutation
Chenxu Guo 1 , Shang-Jui Tsai 1 , Yiwei Ai 1 , Maggie Li 2 , Eduardo Anaya 2 , Andrew Pekosz 2 , Andrea Cox 3 , Stephen J Gould 1
Affiliations
PMID: 36563151 DOI: 10.1126/sciadv.ade5085
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) egress occurs by lysosomal exocytosis. We show that the Spike D614G mutation enhances Spike trafficking to lysosomes, drives Spike-mediated reprogramming of lysosomes, and reduces cell surface Spike expression by ~3-fold. D614G is not a human-specific adaptation. Rather, it is an adaptation to the earlier furin cleavage site insertion (FCSI) mutation that occurred at the genesis of SARS-CoV-2. While advantageous to the virus, furin cleavage of spike has deleterious effects on spike structure and function, inhibiting its trafficking to lysosomes and impairing its infectivity by the transmembrane serine protease 2(TMPRSS2)-independent, endolysosomal pathway. D614G restores spike trafficking to lysosomes and enhances the earliest events in SARS-CoV-2 infectivity, while spike mutations that restore SARS-CoV-2's TMPRSS2-independent infectivity restore spike's trafficking to lysosomes. Together, these and other results show that D614G is an intragenic suppressor of deleterious traits linked to the FCSI and lend additional support to the endolysosomal model of SARS-CoV-2 egress and entry.
Chenxu Guo[SUP] 1 [/SUP], Shang-Jui Tsai[SUP] 1 [/SUP], Yiwei Ai[SUP] 1 [/SUP], Maggie Li[SUP] 2 [/SUP], Eduardo Anaya[SUP] 2 [/SUP], Andrew Pekosz[SUP] 2 [/SUP], Andrea Cox[SUP] 3 [/SUP], Stephen J Gould[SUP] 1 [/SUP]
Affiliations
- PMID: 36563151
- DOI: 10.1126/sciadv.ade5085
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) egress occurs by lysosomal exocytosis. We show that the Spike D614G mutation enhances Spike trafficking to lysosomes, drives Spike-mediated reprogramming of lysosomes, and reduces cell surface Spike expression by ~3-fold. D614G is not a human-specific adaptation. Rather, it is an adaptation to the earlier furin cleavage site insertion (FCSI) mutation that occurred at the genesis of SARS-CoV-2. While advantageous to the virus, furin cleavage of spike has deleterious effects on spike structure and function, inhibiting its trafficking to lysosomes and impairing its infectivity by the transmembrane serine protease 2(TMPRSS2)-independent, endolysosomal pathway. D614G restores spike trafficking to lysosomes and enhances the earliest events in SARS-CoV-2 infectivity, while spike mutations that restore SARS-CoV-2's TMPRSS2-independent infectivity restore spike's trafficking to lysosomes. Together, these and other results show that D614G is an intragenic suppressor of deleterious traits linked to the FCSI and lend additional support to the endolysosomal model of SARS-CoV-2 egress and entry.