Monday, 11 February 2008

Function of vFLIP - a protein from the virus associated with Kaposi's sarcoma

Today's Monday seminar was given by Professor Mary Collins from the Division of Infection and Immunity at University College London's medical school. She described some of her studies of the function and mechanism of vFLIP, a protein from the human herpesvirus 8 (HHV8). This is a cancer-causing (oncogenic) virus and is responsible for the AIDS-associated tumour, Kaposi's sarcoma.

While very many people - about 10-15% of blood donors in London, for example - have been exposed to, and have antibodies for, this virus, it only causes problems in people with defective immune systems. In these people, however, it can cause lymphoma or multicentric Castleman's disease as well as Kaposi's sarcoma. This, however, is now - thanks to HIV and AIDS - one of the commonest cancers worldwide, in fact the commonest in some African countries. AIDS-related Kaposi's sarcoma is fairly rapidly fatal if untreated; however, it can now be controlled very well (although not completely cured) with anti-retroviral therapy.

HHV8 is a large (by viral standards!) double-stranded DNA virus. The protein vFLIP is one of a cluster of proteins expressed while the virus is latent. It binds to a protein called i-kappa kinase gamma in virus-infected cells. This causes the kinase to phosphorylate inhibitors of the cytokine NF-kappa B, leading to the release of NF-kappa B from inhibitor complexes and ultimately the degradation of the inhibitors. This leads to a cascade of gene expression that is essential for the prevention of apoptosis; in contrast, knockdown of vFLIP levels by siRNA will lead to induction of apoptosis. vFLIP is therefore implicated in the survival of virally infected cells.

Endothelial cells that have been infected by HHV8 adopt a characteristic "spindle cell" phenotype. Microarrays have shown that the virus induces complex re-programming of gene transcription in these cells, which is likely to induce this dramatic change in their morphology. Future work will elucidate the precise role of the signal transduction cascade induced by vFLIP in this "morphological reprogramming".

There is no structure available for vFLIP, but there are a large number of kinase structures known. From the UniProt database, the closest to i-kappa kinase is the intracellular Ser/Thr protein kinase domain of Mycobacterium tuberculosis PknB (PDB entry 1MRU).

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