E3 ubiquitin ligases and human papillomavirus-induced carcinogenesis

Abstract

Human papillomavirus (HPV) infection is clinically very common. It is usually a major risk factor in the development of cutaneous benign lesions, cervical cancer and a variety of other malignancies. The biological function of ubiquitination as an intracellular proteasomal-mediated form of protein degradation and an important modulator in the regulation of many fundamental cellular processes has been increasingly recognized over the last decade. HPV proteins have been demonstrated to evolve different strategies to utilize the ubiquitin system for their own purposes. The putative roles of E3 ubiquitin ligases in HPV-induced carcinogenesis have become increasingly apparent, although the mechanisms remain unclear. In this review we provide an update on the mechanisms of the involvement of E3 ubiquitin ligases in HPV-induced carcinogenesis, focusing on their interaction with HPV proteins and their roles in several signalling pathways. Targeting the E3 ubiquitin ligases might offer potential therapeutic strategies for HPV-related diseases in future.

The CXCL12/CXCR4 Signaling Pathway: A New Susceptibility Factor in Human Papillomavirus Pathogenesis

“…This was not associated with an integration of the HPV genome further supporting that disruption of the E2 ORF is not the only mechanism of suppressing E2 and increasing E6 and E7 expression as previously reported in HPV16-induced carcinogenic progression [46]. Such modulations of oncoproteins expression might involve the ubiquitin-proteasome system, which is involved in the degradation of E6 produced by the high-risk types HPV18 and HPV16 [47]. Additionally, the capacity of E6 to interact with certain PDZ domain proteins and phosphoserine-binding proteins involved in cell signaling pathways is a mechanism for regulating E6 stability that is common to diverse high-risk HPV types [48–50].…”

The Ubiquitin-Conjugating System: Multiple Roles in Viral Replication and Infection

“…The rotavirus NSP1 protein leads to β-TrCP ubiquitination and degradation through the recruitment of the ubiquitin-ligase complex Skp-1/Cul1/F-Box (SCF) [45]. Furthermore, small DNA viruses with known oncogenic activity, such as the human papillomavirus (HPV), adenoviruses and polyomaviruses, take control of the cell cycle by usurping specific cellular Ub ligase complexes to target crucial cell cycle regulators such as p53 and the protein of the retinoblastoma (pRB) for degradation [58]. In this way, two of the best studied tumor suppressor cellular pathways are inactivated.…”

HPV Oncoproteins and the Ubiquitin Proteasome System: A Signature of Malignancy?

“…Many human pathologies, such as inflammatory and neurodegenerative diseases and certain cancers are, directly or indirectly, promoted by the deregulation of the UPS [32,44]. An intriguing feature of both HPV oncoproteins, E6 and E7, is their ability to direct many of their cellular substrates for proteasome-mediated degradation [21,45]. Those interactions were either shown or confirmed using methods like co-immunoprecipitation, Glutathione-S-transferase (GST)-fusion protein pull-down, affinity chromatography, Yeast Two Hybrid Assay and/or Tandem Affinity Purification and Gaussia princeps luciferase protein complementation assay.…”

“…Those interactions were either shown or confirmed using methods like co-immunoprecipitation, Glutathione-S-transferase (GST)-fusion protein pull-down, affinity chromatography, Yeast Two Hybrid Assay and/or Tandem Affinity Purification and Gaussia princeps luciferase protein complementation assay. HPV E6 and E7 proteins appear to have evolved various strategies to make use of the ubiquitin system to support the viral lifecycle [45][46][47]. In particular, to avoid apoptosis, E6 mainly targets p53 while, by targeting the pRb, p107 and p130 pocket proteins, E7 induces cell cycle progression [48][49][50].…”

“…There are also additional ubiquitin ligases and other components of the UPS, which are directed for similar activities by the viral oncoproteins [46,[59][60][61][62][63]. Furthermore, HPV oncoprotein interactions with the UPS are not only critical for successful viral replication, but are also necessary for maintenance of the transformed phenotype [15,45]. Studies have shown that interference with components of the UPS has a down-regulatory effect on the ability of HPV-transformed cells to proliferate indefinitely and to avoid apoptosis [46,47,[62][63][64].…”