AKTivation of PI3K/AKT/mTOR signaling pathway by KSHV

Abstract

As an obligate intracellular parasite, Kaposi sarcoma-associated herpesvirus (KSHV) relies on the host cell machinery to meet its needs for survival, viral replication, production, and dissemination of progeny virions. KSHV is a gammaherpesvirus that is associated with three different malignancies: Kaposi sarcoma (KS), and two B cell lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease. KSHV viral proteins modulate the cellular phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which is a ubiquitous pathway that also controls B lymphocyte proliferation and development. We review the mechanisms by which KSHV manipulates the PI3K/AKT/mTOR pathway, with a specific focus on B cells.

Keywords: Akt; B cells; KSHV; PI3K; mTOR.

FIGURE 1

Kaposi sarcoma-associated herpesvirus K1 activates PI3K/AKT/mTOR signaling thereby activating protein synthesis and survival pathways, while inhibiting apoptotic pathways. Orange circles denote phosphorylation.

FIGURE 2

Kaposi sarcoma-associated herpesvirus vGPCR broadly activates PI3K and MAPK pathways, leading to increased production of cytokines and growth factors, with a concurrent increase in cell proliferation, and inhibition of apoptotic pathways. Orange circles denote phosphorylation.

FIGURE 3

Viral proteins enhance cell proliferation by autocrine and paracrine mechanisms. Viral and cellular cytokines and growth factors can activate signaling pathways within the cell they are secreted from (autocrine), or on distant cells that may either be uninfected or latently infected with KSHV (paracrine). RTK, receptor tyrosine kinase.