A conserved domain of the gp85/trans-sialidase family activates host cell extracellular signal-regulated kinase and facilitates Trypanosoma cruzi infection.
Chagas' disease is a chronic, debilitating and incapacitating illness, caused by the protozoan parasite Trypanosoma cruzi when infective trypomastigotes invade host cells. Although the mechanism of trypomastigotes interaction with mammalian cells has been intensively studied, a final and integrated picture of the signal transduction mechanisms involved still remains to be elucidated. Our group has previously shown that the conserved FLY domain (VTVXNVFLYNR), present in all members of the gp85/trans-sialidase glycoprotein family coating the surface of trypomastigotes, binds to cytokeratin 18 (CK18) on the surface of LLC-MK(2) epithelial cells, and significantly increases parasite entry into mammalian cells. Now it is reported that FLY, present on the surface of trypomastigotes or on latex beads binds to CK18, promotes dephosphorylation and reorganization of CK18 and activation of the ERK1/2 signaling cascade culminating in an increase of approximately 9-fold in the number of parasites/cell. Inhibition of ERK1/2 phosphorylation completely blocks the adhesion of FLY to cells and blocks by 57% the host cell infection by T. cruzi. Taken together our results indicate that the conserved FLY domain is an important tool that trypomastigotes have evolved to specific exploit the host cell machinery and guarantee a successful infection.
Magdesian
Margaret H
MH
Instituto de Bioquímica Médica, Av Brigadeiro Trompowsky S/N, bloco H sala 19, CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil. magdesian@bioqmed.ufrj.br
Tonelli
Renata R
RR
Fessel
Melissa R
MR
Silveira
Mariana S
MS
Schumacher
Robert I
RI
Linden
Rafael
R
Colli
Walter
W
Alves
Maria Júlia M
MJ
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053538:Keratin-18 / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009439:Neuraminidase / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D014349:Trypanosoma cruzi / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D014774:Virulence
D006023:Glycoproteins; D053538:Keratin-18; D010446:Peptide Fragments; D015800:Protozoan Proteins; C069715:trans-sialidase; D009439:Neuraminidase