{PDOC52073}
{PS52073; COV_NSP6}
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* Coronavirus Nsp6 transmembrane protein profile *
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Coronaviruses (CoVs)  are  enveloped  positive-strand  RNA viruses that infect
many species, including humans, other mammals, and birds. After infection, the
host may   develop  respiratory,  bowel,  liver,  and  neurological  diseases.
Coronaviruses are divided into four genera: Alphacoronavirus, Betacoronavirus,
Gammacoronavirus, and  Deltacoronavirus.  SARS,  SARS-CoV-2, BatCoV RaTG13 and
Bat-SARS-like coronavirus  (BATSL-CoVZXC21  and  BAT-SL-CoVZC45) belong to the
Sarbecovirus subgenus of Betacoronavirus [E1].

The CoV  replicase  gene encodes two overlapping polyproteins, termed pp1a and
pp1ab, which  mediate  viral  replication  and transcription. The polypeptides
pp1a and  pp1ab  are  processed  by  the action of a main protease (Nsp5) (see
<PDOC51442>) and of one or two papain-like proteases (PLpro) (see <PDOC51124>)
found in  Nsp3  into  non-structural  proteins (Nsps) to form the replication/
transcription complex  (RTC).  Among  them, the replicase proteins Nsp3, Nsp4,
and Nsp6  contain transmembrane (TM)-spanning sequences that are important for
sequestering endoplasmic  reticulum (ER) membranes to form the double-membrane
vesicles which  are  the  site  of  viral RNA synthesis. These double membrane
structures provide  a  protective  environment where viral RNA replication can
occur away from cytoplasmic sensors and defenses [1,2,3].

Nsp4 is  a  glycoprotein  with  four TM segments. Nsp3 anchors its multidomain
protein to  ER  membranes,  likely  using  two  TM segments. Nsp6 contains six
membrane-spanning segments  and  has  an  additionnal  C-terminal  amphipathic
helix, which  likely associates with the ER membrane rather than traverses the
lipid bilayer.  Nsp6  contributes  to  CoV  replication  through  a variety of
mechanisms. Three  major  functions  have  been  reported  for  Nsp6:  (i)  it
dimerizes to  form  replication  organelles,  (ii)  it antagonizes host innate
immune response  by  tampering  with  IFN-I  signaling  pathways, and (iii) it
activates NOD-like  receptor  (NLR)  Family  Pyrin Domain Containing 3 (NLRP3)
inflammasomes by impeding the acidification of lysosomes [1,2,3].

The profile we developed covers the entire Nsp6 protein.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: August 2025 / First entry.

[ 1] Oostra M., Hagemeijer M.C., van Gent M., Bekker C.P., te Lintelo E.G.,
     Rottier P.J., de Haan C.A.
     "Topology and membrane anchoring of the coronavirus replication
     complex: not all  hydrophobic domains of nsp3 and nsp6 are membrane
     spanning."
     J. Virol. 82:12392-12405(2008).
     PubMed=18842706; DOI=10.1128/JVI.01219-08
[ 2] Baliji S., Cammer S.A., Sobral B., Baker S.C.
     "Detection of nonstructural protein 6 in murine coronavirus-infected
     cells and analysis of the transmembrane topology by using
     bioinformatics and molecular approaches."
     J. Virol. 83:6957-6962(2009).
     PubMed=19386712; DOI=10.1128/JVI.00254-09
[ 3] Bills C., Xie X., Shi P.Y.
     "The multiple roles of nsp6 in the molecular pathogenesis of
     SARS-CoV-2."
     Antiviral. Res. 213:105590-105590(2023).
     PubMed=37003304; DOI=10.1016/j.antiviral.2023.105590
[E1] https://viralzone.expasy.org/30?outline=all_by_species

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