eprintid: 10088353
rev_number: 18
eprint_status: archive
userid: 608
dir: disk0/10/08/83/53
datestamp: 2019-12-20 11:46:13
lastmod: 2021-09-17 22:31:42
status_changed: 2019-12-20 11:46:13
type: article
metadata_visibility: show
creators_name: Benfield, CT
creators_name: MacKenzie, F
creators_name: Ritzefeld, M
creators_name: Mazzon, M
creators_name: Weston, S
creators_name: Tate, E
creators_name: Teo, BH
creators_name: Smith, SE
creators_name: Kellam, P
creators_name: Holmes, EC
creators_name: Marsh, M
title: Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
divisions: D77
note: © 2019 Benfield et al. https://creativecommons.org/licenses/by/4.0/
This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0).
abstract: Host interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which are zoonotic and emerging viruses with bats (order Chiroptera) as their natural hosts. We previously demonstrated that microbat IFITM3 is antiviral. Here, we show that bat IFITMs are characterized by strong adaptive evolution and identify a highly variable and functionally important site-codon 70-within the conserved CD225 domain of IFITMs. Mutation of this residue in microbat IFITM3 impairs restriction of representatives of four different virus families that enter cells via endosomes. This mutant shows altered subcellular localization and reduced S-palmitoylation, a phenotype copied by mutation of conserved cysteine residues in microbat IFITM3. Furthermore, we show that microbat IFITM3 is S-palmitoylated on cysteine residues C71, C72, and C105, mutation of each cysteine individually impairs virus restriction, and a triple C71A-C72A-C105A mutant loses all restriction activity, concomitant with subcellular re-localization of microbat IFITM3 to Golgi-associated sites. Thus, we propose that S-palmitoylation is critical for Chiropteran IFITM3 function and identify a key molecular determinant of IFITM3 S-palmitoylation.
date: 2020-01
date_type: published
official_url: https://doi.org/10.26508/lsa.201900542
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1732072
doi: 10.26508/lsa.201900542
pii: 3/1/e201900542
lyricists_name: Marsh, Mark
lyricists_name: Mazzon, Michela
lyricists_id: MCPMA80
lyricists_id: MMAZZ68
actors_name: Marsh, Mark
actors_id: MCPMA80
actors_role: owner
full_text_status: public
publication: Life Science Alliance
volume: 3
number: 1
article_number: e201900542
event_location: United States
issn: 2575-1077
citation:        Benfield, CT;    MacKenzie, F;    Ritzefeld, M;    Mazzon, M;    Weston, S;    Tate, E;    Teo, BH;                 ... Marsh, M; + view all <#>        Benfield, CT;  MacKenzie, F;  Ritzefeld, M;  Mazzon, M;  Weston, S;  Tate, E;  Teo, BH;  Smith, SE;  Kellam, P;  Holmes, EC;  Marsh, M;   - view fewer <#>    (2020)    Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain.                   Life Science Alliance , 3  (1)    , Article e201900542.  10.26508/lsa.201900542 <https://doi.org/10.26508/lsa.201900542>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10088353/1/Benfield%20et%20al.pdf