Researchers in the Biomolecular Interaction group at the Research Center for Natural Sciences investigate signaling enzymes involved in the regulation of cell’s life and death. In their recent study, published in Nature Communications, they were curious about how a herpes viral protein affects cell growth regulating signaling pathways and turns on some enzymes called kinases.

Mór Kaposi, a Hungarian physician, identified a new type of sarcoma in 1872, which was named after him. By the end of the last century, it was found that the disease is caused by herpes virus infection, and the virus was named as Kaposi’s sarcoma herpes virus (KSHV).

Human herpes viruses have been evolving in us for a long time and healthy individuals do not contract the disease despite that they are infected and can spread the virus. Thus, these tamed viruses do not cause epidemics anymore, and this is the reason why researchers found them so interesting as they got to know the host cell’s regulatory circuitry, learned about its weak points, and exploited them for their own good.

The international team elucidated the effect of the KSHV ORF45 protein on human cells by combining classical biochemical methods with in-cell measurements in order to build a computational model suitable to simulate the formation and activity of key kinase complexes.

It was found that the viral protein binds two key kinases carrying out the phosphorylation of proteins simultaneously. This changes the dynamics of protein-protein complex formation ultimately leading to an increase in cell growth pathway activity. In addition, the team determined the X-ray structure of the enzymes bound to viral protein motifs.

The X-ray structure of the complex of KSHV ORF45 (in magenta) bound to RSK2 (teal). Structural images about the virus motifs; RSK binding in salmon, and ERK2 binding in yellow.

These results showed how the KSHV ORF45 protein reconfigures kinase complexes involved in cell growth, moreover, it also revealed hitherto unknown protein-protein interaction surfaces that are utilized under normal physiological conditions but are also preferentially targeted by viral motifs.

Kaposi’s sarcoma herpes virus, similarly to other viruses, attacks the sensitive links in the host cell’s regulatory circuitry. The concrete mechanism is based on molecular mimicry, or imitation, where the viral protein competes with host proteins for binding surfaces on proteins affecting the balance of cell growth and death.

Learning the tricks of these tamed viruses gives us new ideas on how to combat signaling diseases such as cancer, associated with increased cell growth, or chronic inflammation, associated with increased cell death. The group develops new drugs that can target protein surfaces located on those kinases that viral proteins had already explored and exploited, and thus have been proven to play a decisive role in cell growth regulation.

The work was supported by the NRDIO “Frontline” and VEKOP-2.3.3-15-2016-00011 grants.

Anita Alexa, Péter Sok, Fridolin Gross, Krisztián Albert, Evan Kobori, Ádám L. Póti, Gergő Gógl, Isabel Bento, Ersheng Kuang, Susan S. Taylor, Fanxiu Zhu, Andrea Ciliberto, and Attila Reményi.

A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host. Nature Communications 13, 472 (2022). Full text article.

Cover image: Participating scientists from the Biomolecular Interactions Group (Anita Alexa, Péter Sok, Krisztián Albert, Ádám L. Póti and Attila Reményi).