Immunity to commensal papillomaviruses protects against skin cancer

Strickley, John; Messerschmidt, Jonathan L.; Awad, Mary E.; Li, Tiancheng; Hasegawa, Tatsuya; Ha, Dat Thinh; Nabeta, Henry W.; Bevins, Paul A.; Ngo, Kenneth; Asgari, Maryam M.; Nazarian, Rosalynn M.; Neel, Victor A.; Jenson, A. Bennett; Joh, Joongho; Demehri, Shadmehr

doi:10.1038/s41586-019-1719-9

Cited by 115 publications

(70 citation statements)

References 23 publications

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“…However, given the typically transient nature of β-HPV infections, the increased mutational burden may not be particularly consequential. Furthermore, others have suggested that β-HPV infections prime the immune system, helping to prevent NMSCs [ 15 ]. These positions are not mutually exclusive, and should not be interpreted as being in conflict.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, it remains unclear if/how frequently β-HPV infections contribute to NMSC. The “hit and run” model faced further challenges when a recent report suggested β-HPV infections protected against NMSC [ 15 ]. The widespread nature of these infections and their contentious role in tumorigenesis are strong motivating factors for ongoing research into the basic biology of the virus and its gene products.…”

Section: Introductionmentioning

confidence: 99%

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Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

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Gamez

et al. 2020

Cancers

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Cutaneous viral infections occur in a background of near continual exposure to environmental genotoxins, like UV radiation in sunlight. Failure to repair damaged DNA is an established driver of tumorigenesis and substantial cellular resources are devoted to repairing DNA lesions. Beta-human papillomaviruses (β-HPVs) attenuate DNA repair signaling. However, their role in human disease is unclear. Some have proposed that β-HPV promotes tumorigenesis, while others suggest that β-HPV protects against skin cancer. Most of the molecular evidence that β-HPV impairs DNA repair has been gained via characterization of the E6 protein from β-HPV 8 (β-HPV 8E6). Moreover, β-HPV 8E6 hinders DNA repair by binding and destabilizing p300, a transcription factor for multiple DNA repair genes. By reducing p300 availability, β-HPV 8E6 attenuates a major double strand DNA break (DSB) repair pathway, homologous recombination. Here, β-HPV 8E6 impairs another DSB repair pathway, non-homologous end joining (NHEJ). Specifically, β-HPV 8E6 acts by attenuating DNA-dependent protein kinase (DNA-PK) activity, a critical NHEJ kinase. This includes DNA-PK activation and the downstream of steps in the pathway associated with DNA-PK activity. Notably, β-HPV 8E6 inhibits NHEJ through p300 dependent and independent means. Together, these data expand the known genome destabilizing capabilities of β-HPV 8E6.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Bugbee

Gamez

et al. 2020

Cancers

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“…Many of these are phages, but the virome also includes human and animal viruses as well as ERVs and viruses that normally infect plants, archaea and fungi 200,201 . It remains to be understood whether or not viruses can truly be considered commensals given their inherent requirement for replication within host cells, although, when considered from the perspective of a multi-organ system host, viruses can provide benefit by promoting immune development, influencing tissue architecture and promoting immune surveillance against cancer 202,203 . There are multiple animal models and associative human studies in which pathogenic viruses were found to have a role in autoimmunity 158 .…”

Section: Viruses In Autoimmunitymentioning

confidence: 99%

Host–microbiota interactions in immune-mediated diseases

2020

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The immune system evolved not only to fend off pathogens but also to tolerate beneficial microbiota that evolved to live in symbiosis with the host 1. This is perhaps best exemplified from an immunological viewpoint by the paradigm that not only self but also commensal antigens are recognized by regulatory T (T reg) cells that suppress pathological immune responses 2,3. Thus, under immune homeostasis, the immune system tolerates beneficial commensal bacteria but can respond to these same microbiota during tissue disruption or other homeostatic perturbations 4. Self-non-self discrimination of host antigens is a fundamental process that is established and maintained by well-defined central and peripheral tolerance mechanisms (Box 1). How the host immune system develops and responds to the microbiota remains an immunological conundrum of self-non-self discrimination that is poorly understood. Immune-mediated diseases develop in genetically prone individuals when tolerance mechanisms are broken. These diseases are characterized by immunologically mediated tissue damage that is either directed against self-antigens (autoimmunity), transplanted or transfused antigens (alloimmunity), innocuous environmental agents that are inhaled or ingested (allergy) or in the absence of specific antigens (autoinflammation) (Box 2). It is increasingly appreciated that the microbiota directly and indirectly modulates tolerogenic processes that keep inflammatory responses in check. These responses may occur at barrier surfaces

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“…In addition, these β-HPVs are also characterized as co-factors, which, in combination with ultraviolet (UV) irradiation, have been thought to contribute to the development of non-melanoma skin cancers (NMSC) [16]. This was later questioned and it was proposed that loss of T-cell immunity, rather than HPV activity, increased the risk of CSCC in immunosuppressed patients [19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which are critical in maintaining normal cellular functions. E6 and E7 bind directly with certain components of the Ubiquitin Proteasome System (UPS), enabling them to manipulate a number of important cellular pathways. These activities are the means by which HPV establishes an environment supporting the normal viral life cycle, however in some instances they can also lead to the development of malignancy. In this review, we have discussed how E6 and E7 oncoproteins from alpha and beta HPV types interact with the components of the UPS, and how this interplay contributes to the development of cancer.

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Immunity to commensal papillomaviruses protects against skin cancer

Cited by 115 publications

References 23 publications

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Host–microbiota interactions in immune-mediated diseases

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

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