Abstract
Infections with high-risk human papillomaviruses (HPVs) are causally involved in the development of anogenital cancer. HPVs apparently evade the innate immune response of their host cells by dysregulating immunomodulatory factors such as cytokines and chemokines, thereby creating a microenvironment that favors malignancy. One central key player in the immune surveillance interactome is interleukin-1 beta (IL-1β) which not only mediates inflammation, but also links innate and adaptive immunity. Because of its pleiotropic physiological effects, IL-1β production is tightly controlled on transcriptional, post-translational and secretory levels. Here, we describe a novel mechanism how the high-risk HPV16 E6 oncoprotein abrogates IL-1β processing and secretion in a NALP3 inflammasome-independent manner. We analyzed IL-1β regulation in immortalized keratinocytes that harbor the HPV16 E6 and/or E7 oncogenes as well as HPV-positive cervical tumor cells. While in primary and in E7-immortalized human keratinocytes the secretion of IL-1β was highly inducible upon inflammasome activation, E6-positive cells did not respond. Western blot analyses revealed a strong reduction of basal intracellular levels of pro-IL-1β that was independent of dysregulation of the NALP3 inflammasome, autophagy or lysosomal activity. Instead, we demonstrate that pro-IL-1β is degraded in a proteasome-dependent manner in E6-positive cells which is mediated via the ubiquitin ligase E6-AP and p53. Conversely, in E6- and E6/E7-immortalized cells pro-IL-1β levels were restored by siRNA knock-down of E6-AP and simultaneous recovery of functional p53. In the context of HPV-induced carcinogenesis, these data suggest a novel post-translational mechanism of pro-IL-1β regulation which ultimately inhibits the secretion of IL-1β in virus-infected keratinocytes. The clinical relevance of our results was further confirmed in HPV-positive tissue samples, where a gradual decrease of IL-1β towards cervical cancer could be discerned. Hence, attenuation of IL-1β by the HPV16 E6 oncoprotein in immortalized cells is apparently a crucial step in viral immune evasion and initiation of malignancy.
Highlights
High-risk human papillomaviruses (HPVs) are causally responsible for anogenital cancer, both in women and men [1,2]
Our study describes a posttranslationally controlled pathway where E6 mediates proteasomal degradation of interleukin-1 beta (IL-1b) in HPV16-immortalized human keratinocytes
This process depends on the cellular ubiquitin ligase E6-AP and p53 highlighting a novel molecular mechanism of a virus-host interaction that is critical for evading innate immune defense
Summary
High-risk human papillomaviruses (HPVs) are causally responsible for anogenital cancer, both in women and men [1,2]. While in the latter, penile and anal carcinomas are relatively rare, HPV infection is linked in both genders to more than 50% of all oropharyngeal squamous cell carcinomas [1,3,4]. It became evident that viral oncoproteins affect cell cycle regulatory mechanisms and apoptosis, and have a negative impact on the innate immune response of their host and in turn on the respective premalignant microenvironment where unscheduled growth of persistently infected cells is taking place [5,6]. In other words, considering virus-host interactions as a result of a long-lasting evolutionary selection process, HPVs have developed
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