Human Papillomavirus E7 requires the protease calpain to degrade the retinoblastoma protein

Cervical cancers transformed by high risk human papilloma virus (HPV) express the E7 oncoprotein, which accelerates the degradation of the retinoblastoma protein (Rb). Here we show that the E7-mediated degradation of Rb requires the calcium-activated cysteine protease, calpain. E7 bound and activated mu-calpain and promoted cleavage at Rb-810, with mutation of this residue preventing E7-mediated degradation. The calpain cleavage product, Rb1-810, was unable to mediate cell cycle arrest but retained the ability to repress E6/E7 transcription. E7 also promoted the accelerated proteasomal degradation of Rb1-810. Calpain inhibitors reduced the viability of HPV-transformed cells and synergized with cisplatin. Calpain, thus, emerges as a central player in E7-mediated degradation of Rb and represents a potential new drug target for the treatment of HPV-associated lesions.