Abstract
The infectious life cycle of human papillomaviruses (HPVs) is tightly linked to keratinocyte differentiation. Evidence suggests a sophisticated interplay between host gene regulation and virus replication. Alternative splicing is an essential process for host and viral gene expression, and is generally upregulated by serine arginine-rich splicing factors (SRSFs). SRSF activity can be positively or negatively controlled by cycles of phosphorylation/dephosphorylation. Here we show that HPV16 infection leads to accumulation of the paradigm SRSF protein, SRSF1, in the cytoplasm in a keratinocyte differentiation-specific manner. Moreover, HPV16 infection leads to increased levels of cytoplasmic and nuclear phosphorylated SRSF1. SR protein kinase 1 (SRPK1) phosphorylates SRSF1. Similar to HPV upregulation of SRSF1, we demonstrate HPV upregulation of SRPK1 via the viral E2 protein. SRPK1 depletion or drug inhibition of SRPK1 kinase activity resulted in reduced levels of SRSF1, suggesting that phosphorylation stabilizes the protein in differentiated HPV-infected keratinocytes. Together, these data indicate HPV infection stimulates the SRPK1–SRSF axis in keratinocytes.
Highlights
Human papillomaviruses (HPVs) infect cutaneous and mucosal epithelia and cause mainly benign lesions
We examined the location of the HPV-u pregulated serine arginine-rich splicing factors (SRSFs) protein SRSF1 in undifferentiated and differentiated HPV type 16 (HPV16)-infected W12E cells
Involucrin levels were detected only in differentiated cell populations as expected. These data suggest that HPV16 infection causes SRSF1 protein to accumulate in the cytoplasm of differentiated keratinocytes
Summary
Human papillomaviruses (HPVs) infect cutaneous and mucosal epithelia and cause mainly benign lesions (warts). A subset of HPVs which infect the anogenital epithelia can cause preneoplastic disease, which in rare cases can progress to cancers, most notably cervical cancer [1]. The most prevalent HPV worldwide is HPV type 16 (HPV16). HPV16 is responsible for 55 % of cases of cervical cancer but is associated with over 30 % of oropharyngeal cancers, which is prevalent in men [2]. Much is known about the cancer-causing properties of HPV16, many aspects of the viral life cycle and its interaction with the host epithelial cell (keratinocyte) remain unclear. Our understanding of how the virus utilizes host gene expression mechanisms during its replicative life cycle remains incomplete
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