Recent data highlight thepresence, in HIV-1 seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. Weinvestigated the mechanisms responsible for the functional disparity on B cells between a wild-typep17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutationat position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confera 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 position76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bondnetwork. This generates a conformational shift in the p17 R76G mutant which enables a functionalepitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a stillunknown receptor(s). Our findings offer new opportunities to understand the molecular mechanismsaccounting for the B-cell growth-promoting activity of vp17s.
A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17
MARSICO, Stefania;
2017-01-01
Abstract
Recent data highlight thepresence, in HIV-1 seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. Weinvestigated the mechanisms responsible for the functional disparity on B cells between a wild-typep17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutationat position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confera 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 position76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bondnetwork. This generates a conformational shift in the p17 R76G mutant which enables a functionalepitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a stillunknown receptor(s). Our findings offer new opportunities to understand the molecular mechanismsaccounting for the B-cell growth-promoting activity of vp17s.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
