Following an Infection Focal Adhesion Kinase Binds to the HPV E2 Protein to Regulate the Beginning of Replication

Elena Sarawat^*
*Correspondence: Elena Sarawat, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA, Email:

Introduction

Human Papillomavirus (HPV) is a widespread pathogen responsible for a range of infections in humans, including genital warts and various types of cancers, most notably cervical cancer. HPV infection is characterized by its ability to manipulate host cellular machinery to facilitate its replication and persistence. One of the crucial players in this process is the HPV E2 protein, which plays a central role in regulating viral replication. Recent research has uncovered an intriguing connection between Focal Adhesion Kinase (FAK) and the HPV E2 protein. FAK, a cytoplasmic tyrosine kinase, is typically associated with cellular adhesion and migration. However, emerging evidence suggests that FAK also has a vital role in regulating the initiation of HPV replication. This article delves into the fascinating interplay between FAK and HPV E2 protein, shedding light on how this interaction contributes to the regulation of viral replication. Human Papillomaviruses are a family of small, non-enveloped, double-stranded DNA viruses. These viruses are highly prevalent and infect the cutaneous and mucosal epithelia, leading to various clinical manifestations, ranging from benign warts to malignant cancers. HPV infections are classified into two categories based on their oncogenic potential low-risk and high-risk types. Low-risk types primarily cause benign lesions, such as genital warts, while high-risk types are associated with the development of cervical and other anogenital cancers [1].

Description

The HPV life cycle is closely intertwined with the differentiation program of the host keratinocytes, which are the primary target cells for the virus. The virus enters the host cell through micro-abrasions in the epithelial tissue and subsequently establishes a persistent infection. Key to this process is the regulation of viral replication, which is tightly controlled to avoid detection by the host's immune system. The HPV E2 protein is a multifunctional viral protein that plays a pivotal role in controlling viral replication. It functions as a transcriptional regulator by binding to specific sequences within the viral genome known as the E2 binding sites. E2's primary role is to repress the viral oncogenes E6 and E7, which are critical for the transformation of infected cells and the development of cancer [2].

Additionally, E2 has a role in the initiation of viral DNA replication. It forms a complex with the viral helicase E1 and helps tether the E1 helicase to the viral origin of replication, known as the ori. This interaction is essential for the recruitment of cellular factors necessary for DNA replication initiation. Therefore, E2 acts as a key regulator of viral replication, ensuring that it occurs at the right time during the viral life cycle. Focal Adhesion Kinase (FAK) is a cytoplasmic protein kinase that has primarily been associated with cellular processes such as adhesion and migration. FAK is activated in response to integrin engagement with the extracellular matrix (ECM) and growth factor signaling. Upon activation, FAK becomes autophosphorylated at specific tyrosine residues and acts as a scaffold for various signaling molecules, including Src kinase, leading to downstream signaling events [3].

FAK is essential for the formation of focal adhesions, which are large protein complexes that link the ECM to the actin cytoskeleton. These complexes provide cells with the ability to sense their physical environment and play a crucial role in processes like cell motility and tissue remodeling. In normal physiological conditions, FAK regulates these processes to maintain tissue integrity and repair. Recent studies have uncovered a previously unrecognized role for FAK in the regulation of HPV replication. This unexpected connection between a cellular adhesion molecule and a viral replication protein highlights the complex interplay between viruses and their hosts [4,5].

Conclusion

The interplay between viruses and host cells is a dynamic and intricate process. Human Papillomavirus, with its association with cervical cancer and other malignancies, exemplifies the importance of understanding these interactions. Recent research has unveiled a surprising connection between the cellular adhesion molecule Focal Adhesion Kinase (FAK) and the HPV E2 protein, a key regulator of viral replication. This interaction sheds light on the complex mechanisms by which HPV manipulates host cell machinery to its advantage. While much remains to be discovered about the precise molecular details of the FAK-E2 interaction and its role in HPV replication, the emerging evidence underscores the need for further investigation. Unraveling the intricacies of this interaction may not only enhance our understanding of HPV biology but also pave the way for innovative antiviral strategies aimed at disrupting the viral life cycle and preventing HPV-associated diseases. As research in this area progresses, the potential for new therapeutic interventions against HPV infections and associated cancers becomes increasingly promising.

FAK Activation in Response to HPV Infection: Understanding how FAK becomes activated in response to HPV infection is a crucial aspect of this interaction. While the precise mechanisms are still being elucidated, it is likely that the virus induces changes in host cell behavior, possibly disrupting cellular adhesion and the extracellular matrix. This activation of FAK may serve as a defense mechanism, allowing the virus to manipulate host cell processes for its own benefit. The FAK-E2 Interaction: The direct interaction between FAK and the HPV E2 protein raises questions about the functional consequences of this association. It is noteworthy that this interaction does not interfere with E2's primary role as a transcriptional regulator but rather influences its function in the initiation of viral DNA replication. This suggests that the virus has evolved to exploit FAK's signaling capabilities for its replication needs.

Acknowledgement

None.

Conflict of Interest

There are no conflicts of interest by author.

References

1. McKinney, Caleb C., Katherine L. Hussmann and Alison A. McBride. “The role of the DNA damage response throughout the papillomavirus life cycle.” Viruses 7 (2015): 2450.

Google Scholar, Crossref, Indexed at

2. Hong, Shiyuan and Laimonis A. Laimins. “Regulation of the life cycle of HPVs by differentiation and the DNA damage response.” Future Microbiol 8 (2013): 1547–1557.

Google Scholar, Crossref, Indexed at

3. Münger, Karl, Amy Baldwin, Kirsten M. Edwards and Hiroyuki Hayakawa, et al. “Mechanisms of Human Papillomavirus-induced oncogenesis.” J Virol 78 (2004): 11451–11460.

Google Scholar, Crossref, Indexed at

4. Webster, Kenneth, Joanna Parish, Maya Pandya and Peter L. Stern, et al. “The Human Papillomavirus (HPV) 16 E2 protein induces apoptosis in the absence of other hpv proteins and via a p53-dependent pathway.” J Biol Chem 275 (2000): 87–94.

Google Scholar, Crossref, Indexed at

5. Moody, Cary A. and Laimonis A. Laimins. “Human Papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation.” PLoS Pathog 5 (2009): e1000605.
 

Google Scholar, Crossref, Indexed at