A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17

Cinzia Giagulli, Pasqualina D'Ursi, Wangxiao He, Simone Zorzan, Francesca Caccuri, Kristen Varney, Alessandro Orro, Stefania Marsico, Benoît Otjacques, Carlo Laudanna, Luciano Milanesi, Riccardo Dolcetti, Simona Fiorentini, Wuyuan Lu, Arnaldo Caruso

Research output: Contribution to journalArticle

Abstract

Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s.

Original languageEnglish
Article number6555
Number of pages13
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

Keywords

  • hiv
  • lymphoma

ASJC Scopus subject areas

  • General

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  • Cite this

    Giagulli, C., D'Ursi, P., He, W., Zorzan, S., Caccuri, F., Varney, K., Orro, A., Marsico, S., Otjacques, B., Laudanna, C., Milanesi, L., Dolcetti, R., Fiorentini, S., Lu, W., & Caruso, A. (2017). A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17. Scientific Reports, 7(1), [6555]. https://doi.org/10.1038/s41598-017-06848-y