Abstract
The cornification of keratinocytes on the surface of skin and oral epithelia is associated with the degradation of nuclear DNA. The endonuclease DNase1L2 and the exonuclease Trex2 are expressed specifically in cornifying keratinocytes. Deletion of DNase1L2 causes retention of nuclear DNA in the tongue epithelium but not in the skin. Here we report that lack of Trex2 results in the accumulation of DNA fragments in the cytoplasm of cornifying lingual keratinocytes and co-deletion of DNase1L2 and Trex2 causes massive accumulation of DNA fragments throughout the cornified layers of the tongue epithelium. By contrast, cornification-associated DNA breakdown was not compromised in the epidermis. Aberrant retention of DNA in the tongue epithelium was associated neither with enhanced expression of DNA-driven response genes, such as Ifnb, Irf7 and Cxcl10, nor with inflammation. Of note, the expression of Tlr9, Aim2 and Tmem173, key DNA sensor genes, was markedly lower in keratinocytes and keratinocyte-built tissues than in macrophages and immune tissues, and DNA-driven response genes were not induced by introduction of DNA in keratinocytes. Altogether, our results indicate that DNase1L2 and Trex2 cooperate in the breakdown and degradation of DNA during cornification of lingual keratinocytes and aberrant DNA retention is tolerated in the oral epithelium.
Highlights
Cornification is a mechanistically unique mode of programmed cell death that is restricted to keratinocytes undergoing terminal differentiation
The Trex[2] exonuclease and the DNase1L2 endonuclease are expressed in differentiated keratinocytes
Among the multiple genes displaying DNA nuclease activity, the Trex[2] exonuclease and the endonuclease DNase1L2 are expressed in keratinocytes[13,14,18,19]
Summary
Cornification is a mechanistically unique mode of programmed cell death that is restricted to keratinocytes undergoing terminal differentiation. While the appearance of parakeratosis in diverse skin disorders suggests that the degradation of the nucleus can be disturbed by multiple molecular triggers, the molecular regulation of cornification-associated breakdown of nuclear components and the etiological roles of these processes have remained poorly characterized. The keratinocyte-specific endonuclease DNase1L2 is required for nuclear DNA degradation in human keratinocytes differentiating in skin models in vitro[13]. Deletion of the lysosomal endonuclease DNase[2] impaired DNA degradation during holocrine secretion of sebum but did not abrogate cornification-associated DNA breakdown in the interfollicular epidermis[15,16]. The loss of the exonuclease Trex[1], which degrades DNA in the cytosol of many cell types, results in DNA accumulation leading to the induction of type I interferon (IFN) responses and autoimmunity[26,27,28,29,30].
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