Effect of 12- O -tetradecanoyl-phorbol ester and incisional wounding on neuropsin mRNA and its protein expression in murine skin

Kitayoshi, Hikaru; Inoue, N.; Kuwae, Katsuki; Chen, Z.-L.; Sato, Hiroaki; Ohta, Tomohiro; Hosokawa, Keiichi; Itami, Satoshi; Yoshikawa, Kunihiko; Yoshida, Shigetaka; Shiosaka, Sadao

doi:10.1007/s004030050418

Cited by 14 publications

(22 citation statements)

References 23 publications

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“…Like other kallikreins, KLK8 exhibits a broad expression profile in many tissues. However, KLK8 is most prominently expressed in the brain, the mucosa, and the skin, where it has roles in tissue homeostasis, desquamation of cells, ECM remodelling, and wound healing (67,72,73). Since it has been speculated that HPV particles may be structurally primed for entry already at the site of assembly in the upper layers of the epithelium (25), authentic HPV might be cleaved by KLK8 at the site of desquamation prior to transmission.…”

Section: Discussionmentioning

confidence: 99%

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

Cerqueira

Ventayol

Vogeley

et al. 2015

J Virol

104

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The entry of human papillomaviruses into host cells is a complex process. It involves conformational changes at the cell surface, receptor switching, internalization by a novel endocytic mechanism, uncoating in endosomes, trafficking of a subviral complex to the Golgi complex, and nuclear entry during mitosis. Here, we addressed how the stabilizing contacts in the capsid of human papillomavirus 16 (HPV16) may be reversed to allow uncoating of the viral genome. Using biochemical and cell-biological analyses, we determined that the major capsid protein L1 underwent proteolytic cleavage during entry. In addition to a dispensable cathepsin-mediated proteolysis that occurred likely after removal of capsomers from the subviral complex in endosomes, at least two further proteolytic cleavages of L1 were observed, one of which was independent of the low-pH environment of endosomes. This cleavage occurred extracellularly. Further analysis showed that the responsible protease was the secreted trypsin-like serine protease kallikrein-8 (KLK8) involved in epidermal homeostasis and wound healing. Required for infection, the cleavage was facilitated by prior interaction of viral particles with heparan sulfate proteoglycans. KLK8-mediated cleavage was crucial for further conformational changes exposing an important epitope of the minor capsid protein L2. Occurring independently of cyclophilins and of furin that mediate L2 exposure, KLK8-mediated cleavage of L1 likely facilitated access to L2, located in the capsid lumen, and potentially uncoating. Since HPV6 and HPV18 also required KLK8 for entry, we propose that the KLK8-dependent entry step is conserved. IMPORTANCEOur analysis of the proteolytic processing of incoming HPV16, an etiological agent of cervical cancer, demonstrated that the capsid is cleaved extracellularly by a serine protease active during wound healing and that this cleavage was crucial for infection. The cleavage of L1 is one of at least four structural alterations that prime the virus extracellularly for receptor switching, internalization, and possibly uncoating. This step was also important for HPV6 and HPV18, which may suggest that it is conserved among the papillomaviruses. This study advances the understanding of how HPV16 initially infects cells, strengthens the notion that wounding facilitates infection of epidermal tissue, and may help the development of antiviral measures. Human papillomaviruses (HPVs) comprise a large family of small, nonenveloped DNA viruses with transforming potential. HPVs selectively infect basal keratinocytes of stratified skin and mucosal epithelia and persist, mostly without clinical symptoms, in virtually every part of the human skin. The biological costs of HPV persistence range from benign papilloma and genital warts over preneoplastic lesions to anogenital or oropharyngeal cancers (1). In fact, infection by the so-called "high-risk" HPV causes about 5% of all human cancers (2). Of these, cervical cancers are the most prevalent. However, HPV-associated oropharyngea...

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Section: Discussionmentioning

confidence: 99%

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

Cerqueira

Ventayol

Vogeley

et al. 2015

J Virol

104

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“…This was particularly evident for the sizeable group of extracellular matrix-degrading proteases and their receptors and inhibitors, whose expression is known to be strongly upregulated (although stoichiometrically still being present in minute amounts) in migrating keratinocytes at the wound edge. These included the urokinase plasminogen activator, urokinase plasminogen activator receptor, plasminogen activator inhibitor-1, matriptase/MT-SP1, neuropsin, and matrix metalloproteinases 3, 9, 10, and 13 (Romer et al, 1996;Madlener et al, 1998;Kitayoshi et al, 1999;Lund et al, 1999, unpublished data). The improvement of methods for RNA isolation, reverse transcription, and hybridization, and the use of more sensitive arrays should overcome such limitations in sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Laser capture microdissection-based in vivo genomic profiling of wound keratinocytes identifies similarities and differences to squamous cell carcinoma

et al. 2003

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“…A previous study showed that Klk8 mRNA was induced by an external stimulus, such as the application of 12-O-tetradecanoylphorbol-13-acetate (TPA), which causes epidermal proliferation and hyperkeratosis like psoriasis of human skin (15). In the present study, we used TPA to compare the reaction of WT and Klk8 Ϫ/Ϫ mouse skin.…”

mentioning

confidence: 95%

Kallikrein 8 Is Involved in Skin Desquamation in Cooperation with Other Kallikreins

Kishibe

Bandô²,

Terayama³

et al. 2007

Journal of Biological Chemistry

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Kallikrein type serine proteases, KLK8/neuropsin, KLK6, and KLK7, have been implicated in the proliferation and differentiation of epidermal keratinocytes and in the pathogenesis of psoriasis. However, their mechanistic roles in these processes remain largely unknown. We applied 12-O-tetradecanoylphorbol-13-acetate on the wild type (WT) and the Klk8 gene-disrupted (Klk8 ؊/؊ ) mouse skin, inducing keratinocyte proliferation similar to the human psoriatic lesion. Klk8 mRNA as well as Klk6 and Klk7 mRNA were up-regulated after 12-O-tetradecanoylphorbol-13-acetate application in the WT mice. In contrast, Klk8؊/؊ mice showed minimum increases of Klk6 and Klk7 transcripts, the proteins, and enzymatic activities. Relative to the WT, the Klk8 ؊/؊ skin showed less proliferation and an increase in the number of cell layers in the stratum corneum. However, overexpression of Klk8 by adenovirus vector in knock-out keratinocytes did not result in an increase in Klk6 or Klk7 mRNA. The inefficient cleavage of adhesion molecules DSG1 and CDSN in Klk8 ؊/؊ skin contributes to a delay in corneocyte shedding, resulting in the hyperkeratosis phenotype. We propose that in psoriatic lesion, KLK8 modulates hyperproliferation and prevents excessive hyperkeratosis by shedding the corneocytes.

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Effect of 12- O -tetradecanoyl-phorbol ester and incisional wounding on neuropsin mRNA and its protein expression in murine skin

Cited by 14 publications

References 23 publications

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

Laser capture microdissection-based in vivo genomic profiling of wound keratinocytes identifies similarities and differences to squamous cell carcinoma

Kallikrein 8 Is Involved in Skin Desquamation in Cooperation with Other Kallikreins

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