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Signaling by interferon-gamma stimulates anti-viral responses and tumor suppression through the heterodimeric interferon-gamma receptor. Signaling is initiated by binding of interferon-gamma to its receptor, activating the receptor-associated JAK2 tyrosine kinase to phosphorylate STAT transcription factors that activate interferon responsive genes. Molecular chaperones that modulate or alter protein folding interact with different components of the interferon signaling pathway. One chaperone that modulates interferon signaling is hTid-1, a member of the DnaJ family of chaperones and a co-chaperone for the heat shock protein Hsp70, another molecular chaperone. hTid-1 was found in a two-hybrid screen to bind to JAK2 and also to interact with the interferon-gamma receptor. In addition, hTid-1 and JAK2 also interact with Hsp70. Overexpression of hTid-1 represses transcriptional activation by interferon-gamma and Hsp70 dissociates from these proteins when interferon is added to cells, suggesting that Hsp70 holds Jak2 in an inactive conformation prior to ligand activation, and is released in the presence of agonist to allow the activation of Jak-2 and downstream pathways. hTid-1 and Hsp-70 interact with other signaling proteins as well. One of these is Tax, a protein encoded by the HTLV-1 virus that binds to hTid-1. hTid-1 also represses NF-kB activation by blocking the phosphorylation and inactivation of I-kappaB by the IkappaB kinase beta. Hsp70 plays a significant role in protein unfolding for entry into mitochondria and also interacts with tumor suppressor gene products to produce their anti-proliferative activity. One of the actions of interferon is to induce apoptosis of infected target cells, in part through a mitochondrial dependent mechanism. An interaction between interferon signaling and Hsp70 may alter this mitochondrial apoptosis pathway, perhaps playing a role in interferon-mediated apoptosis of infected or transformed cells. The HTLV-1 Tax protein that interacts with Hsp70 blocks mitochondrial induced apoptosis, providing a protection against interferon-mediated cellular defenses. (This definition may be outdated - see the DesignNote.)
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