https://www.ncbi.nlm.nih.gov/pubmed/28768865
Taustaa E3 ubikitiiniligaaseista, joita ihmisellä on luonnollisen immuunipuolustuksensa arsenaalissa.
- RING-type E3 ligases
- ( Single type, esim. Co-Cbl, MDM2, BRCA1.
- RBR type (RING between RING)
- TRIM type( Näitä on ainakin 1-76, joku sanoo että 82)
- Cullin type (SCF-type/VHL-type, BTB-type)
- APL/cyclocome
- RING type E3, U-box type E3 (CHIP, E4B, E4A..)
- HECT type E3
- CE6A8, Nedd 4, Smurf1/2...
- Unclassified E3
- TAF250, A20, IpaH family, Sde A ...
TRIM-tyyppisitä olen kirjoitanut musitiin Solusykliblogiini, lähinnä onkologian kannalta.
nyt katson mitä tästä HECT-tyyppisestä E3 ligaasista snotaan Ebolaviruksen kannalta.
.............
LÄHDE: Viimesyksyinen artikkeli PubMed:ssä. UBIKITIINILIGAASI WWP1 tekee interaktion Ebolavirusksen VP24 proteiinin kanssa ja näin säätyy virionien pääsy solusta ulos.
J Virol. 2017 Sep 27;91(20). pii: e00812-17. doi: 10.1128/JVI.00812-17. Print 2017 Oct 15.
Ubiquitin Ligase WWP1 Interacts with Ebola Virus VP40 To Regulate Egress.
Han Z1, Sagum CA2, Takizawa F1, Ruthel G1, Berry CT1, Kong J1, Sunyer JO1, Freedman BD1, Bedford MT2, Sidhu SS3, Sudol M4, Harty RN5.
Abstract
Ebola virus (EBOV) is a member of the Filoviridae
family and the cause of hemorrhagic fever outbreaks. The EBOV VP40
(eVP40) matrix protein is the main driving force for virion assembly and
budding. Indeed, expression of eVP40 alone in mammalian cells results
in the formation and budding of virus-like particles (VLPs) which mimic
the budding process and morphology of authentic, infectious EBOV.
To complete the budding process, eVP40 utilizes its PPXY L-domain motif to recruit a specific subset of host proteins containing one or more modular WW domains that then function to facilitate efficient production and release of eVP40 VLPs.
In this report, we identified additional host WW-domain interactors by screening for potential interactions between mammalian proteins possessing one or more WW domains and WT or PPXY mutant peptides of eVP40.
We identified the HECT family E3 ubiquitin ligase WWP1 and all four of its WW domains as strong interactors with the PPXY motif of eVP40. The eVP40-WWP1 interaction was confirmed by both peptide pulldown and coimmunoprecipitation assays, which also demonstrated that modular WW domain 1 of WWP1 was most critical for binding to eVP40.
Importantly, the eVP40-WWP1 interaction was found to be biologically relevant for VLP budding since
(i) small interfering RNA (siRNA) knockdown of endogenous WWP1 resulted in inhibition of eVP40 VLP egress,
(ii) coexpression of WWP1 and eVP40 resulted in ubiquitination of eVP40 and a subsequent increase in eVP40 VLP egress,
and (iii) an enzymatically inactive mutant of WWP1 (C890A) did not ubiquitinate eVP40 or enhance eVP40 VLP egress.
Last, our data show that ubiquitination of eVP40 by WWP1 enhances egress of VLPs and concomitantly decreases cellular levels of higher-molecular-weight oligomers of eVP40.
In sum, these findings contribute to our fundamental understanding of the functional interplay between host E3 ligases, ubiquitination, and regulation of EBOV VP40-mediated egress.
IMPORTANCE Ebola virus (EBOV) is a high-priority, emerging human pathogen that can cause severe outbreaks of hemorrhagic fever with high mortality rates. As there are currently no approved vaccines or treatments for EBOV, a better understanding of the biology and functions of EBOV-host interactions that promote or inhibit viral budding is warranted.
Here, we describe a physical and functional interaction between EBOV VP40 (eVP40) and WWP1, a host E3 ubiquitin ligase that ubiquitinates VP40 and regulates VLP egress. This viral PPXY-host WW domain-mediated interaction represents a potential new target for host-oriented inhibitors of EBOV egress.
To complete the budding process, eVP40 utilizes its PPXY L-domain motif to recruit a specific subset of host proteins containing one or more modular WW domains that then function to facilitate efficient production and release of eVP40 VLPs.
In this report, we identified additional host WW-domain interactors by screening for potential interactions between mammalian proteins possessing one or more WW domains and WT or PPXY mutant peptides of eVP40.
We identified the HECT family E3 ubiquitin ligase WWP1 and all four of its WW domains as strong interactors with the PPXY motif of eVP40. The eVP40-WWP1 interaction was confirmed by both peptide pulldown and coimmunoprecipitation assays, which also demonstrated that modular WW domain 1 of WWP1 was most critical for binding to eVP40.
Importantly, the eVP40-WWP1 interaction was found to be biologically relevant for VLP budding since
(i) small interfering RNA (siRNA) knockdown of endogenous WWP1 resulted in inhibition of eVP40 VLP egress,
(ii) coexpression of WWP1 and eVP40 resulted in ubiquitination of eVP40 and a subsequent increase in eVP40 VLP egress,
and (iii) an enzymatically inactive mutant of WWP1 (C890A) did not ubiquitinate eVP40 or enhance eVP40 VLP egress.
Last, our data show that ubiquitination of eVP40 by WWP1 enhances egress of VLPs and concomitantly decreases cellular levels of higher-molecular-weight oligomers of eVP40.
In sum, these findings contribute to our fundamental understanding of the functional interplay between host E3 ligases, ubiquitination, and regulation of EBOV VP40-mediated egress.
IMPORTANCE Ebola virus (EBOV) is a high-priority, emerging human pathogen that can cause severe outbreaks of hemorrhagic fever with high mortality rates. As there are currently no approved vaccines or treatments for EBOV, a better understanding of the biology and functions of EBOV-host interactions that promote or inhibit viral budding is warranted.
Here, we describe a physical and functional interaction between EBOV VP40 (eVP40) and WWP1, a host E3 ubiquitin ligase that ubiquitinates VP40 and regulates VLP egress. This viral PPXY-host WW domain-mediated interaction represents a potential new target for host-oriented inhibitors of EBOV egress.
KEYWORDS:
E3 ubiquitin ligase; Ebola virus; L-domain; PPXY; VLPs; VP40; WW domain;WWP1; https://www.ncbi.nlm.nih.gov/gene/11059
budding
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