Martinez-Noel G, Galligan JT, Sowa ME, Arndt V, Overton TM, Harper JW, Howley PM

The E6AP ubiquitin-ligase catalyzes the high risk Human Papillomaviruses E6-mediated ubiquitylation of p53 contributing to the neoplastic progression of cells infected by these viruses. Defects in the activity and the dosage of E6AP are linked to Angelman Syndrome and to Autism Spectrum Disorders respectively, highlighting the need for precise control ...

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of this enzyme. With the exception of HERC2, which modulates the ubiquitin-ligase activity of E6AP, little is known about the regulation or function of E6AP normally. Using a proteomic approach, we have identified and validated several new E6AP interacting proteins, including HIF1AN, NEURL4 and MAPK6. E6AP exists as part of several different protein complexes including the proteasome and an independent high molecular weight complex containing HERC2, NEURL4 and MAPK6. In examining the functional consequence of its interaction with the proteasome, we found that UBE3C (another proteasome-associated ubiquitin-ligase), but not E6AP, contributes to proteasomal processivity in mammalian cells. We also found that E6 associates with the HERC2 containing high molecular weight complex through its binding to E6AP. These proteomic studies reveal a level of complexity for E6AP that has not been previously appreciated and identify a number of new cellular proteins through which E6AP may be regulated or functioning.

Date: May. 29, 2012

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