Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17

Francesca Caccuri, Maria Luisa Iaria, Federica Campilongo, Kristen Varney, Alessandro Rossi, Stefania Mitola, Silvia Schiarea, Antonella Bugatti, Pietro Mazzuca, Cinzia Giagulli, Simona Fiorentini, Wuyuan Lu, Mario Salmona, Arnaldo Caruso

Research output: Contribution to journalArticle

Abstract

The human immune deficiency virus type 1 (HIV-1) matrix protein p17 (p17), although devoid of a signal sequence, is released by infected cells and detected in blood and in different organs and tissues even in HIV-1-infected patients undergoing successful combined antiretroviral therapy (cART). Extracellularly, p17 deregulates the function of different cells involved in AIDS pathogenesis. The mechanism of p17 secretion, particularly during HIV-1 latency, still remains to be elucidated. A recent study showed that HIV-1-infected cells can produce Gag without spreading infection in a model of viral latency. Here we show that in Gag-expressing cells, secretion of biologically active p17 takes place at the plasma membrane and occurs following its interaction with phosphatidylinositol-(4,5)-bisphosphate and its subsequent cleavage from the precursor Gag (Pr55Gag) operated by cellular aspartyl proteases. These enzymes operate a more complex Gag polypeptide proteolysis than the HIV-1 protease, thus hypothetically generating slightly truncated or elongated p17s in their C-terminus. A 17 C-terminal residues excised p17 was found to be structurally and functionally identical to the full-length p17 demonstrating that the final C-terminal region of p17 is irrelevant for the protein's biological activity. These findings offer new opportunities to identify treatment strategies for inhibiting p17 release in the extracellular microenvironment.

Original languageEnglish
Article number38027
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Dec 1 2016

ASJC Scopus subject areas

  • General

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    Caccuri, F., Iaria, M. L., Campilongo, F., Varney, K., Rossi, A., Mitola, S., Schiarea, S., Bugatti, A., Mazzuca, P., Giagulli, C., Fiorentini, S., Lu, W., Salmona, M., & Caruso, A. (2016). Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17. Scientific Reports, 6, [38027]. https://doi.org/10.1038/srep38027