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TGF-? mimic proteins form an extended gene family in the murine parasite
Heligmosomoides polygyrus
#MMPMID29510118
Smyth DJ
; Harcus Y
; White MPJ
; Gregory WF
; Nahler J
; Stephens I
; Toke-Bjolgerud E
; Hewitson JP
; Ivens A
; McSorley HJ
; Maizels RM
Int J Parasitol
2018[Apr]; 48
(5
): 379-385
PMID29510118
show ga
We recently reported the discovery of a new parasite-derived protein that
functionally mimics the immunosuppressive cytokine transforming growth factor
(TGF)-?. The Heligmosomoides polygyrus TGF-? Mimic (Hp-TGM) shares no homology to
any TGF-? family member, however it binds the mammalian TGF-? receptor and
induces expression of Foxp3, the canonical transcription factor of both mouse and
human regulatory T cells. Hp-TGM consists of five atypical Complement Control
Protein (CCP, Pfam 00084) domains, each lacking certain conserved residues and
12-15 amino acids longer than the 60-70 amino acids consensus domain, but with a
recognizable 3-cysteine, tryptophan, cysteine motif. We now report on the
identification of a family of nine related Hp-TGM homologues represented in the
secreted proteome and transcriptome of H. polygyrus. Recombinant proteins from
five of the nine new TGM members were tested for TGF-? activity, but only two
were functionally active in an MFB-F11 reporter assay, and by the induction of T
cell Foxp3 expression. Sequence comparisons reveal that proteins with functional
activity are similar or identical to Hp-TGM across the first three CCP domains,
but more variable in domains 4 and 5. Inactive proteins diverged in all domains,
or lacked some domains entirely. Testing truncated versions of Hp-TGM confirmed
that domains 1-3 are essential for full activity in vitro, while domains 4 and 5
are not required. Further studies will elucidate whether these latter domains
fulfill other functions in promoting host immune regulation during infection and
if the more divergent family members play other roles in immunomodulation.
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