Recovery from common mechanical stresses on the skin can be hindered by diseases, such as epidermolysis bullosa simplex (EBS), that affect protein folding. Mutations in keratin that cause one EBS lead to the formation of irregular protein ‘clumps’ within cells, similar to those observed in Parkinson’s disease and Alzheimer’s disease.
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Cells called keratinocytes compose the vast majority of the outermost layer of the skin, and represent the body’s first line of defense against the slings and arrows of the outside world. However, certain disorders undermine the capacity of keratinocytes to maintain a unified front; for example, patients with severe epidermolysis bullosa simplex (EBS) routinely develop blisters and sores from even minor traumas.
The culprit underlying EBS is a mutation that disrupts the assembly of keratin proteins K5 and K14, which contribute to the ‘intermediate filaments’ that reinforce cellular structure. However, David Russell at the University of Dundee in the United Kingdom recently found evidence that these mutations may do more than undermine structural integrity. “When I seriously damaged [keratinocytes], I noticed that cells with mutant keratin seemed to survive whereas a larger proportion of wild-type cells died after stretching,” he says.
Russell subsequently partnered with E. Birgitte Lane at the A*STAR Institute of Medical Biology in Singapore to characterize how EBS-associated mutations affect the keratinocyte response to tension. Their experiments using a mechanical device that physically deforms cultured cell layers confirmed that keratin-mutant cells (KEB-7) are significantly less likely to undergo cell death, or apoptosis, in response to stretching, and identified a signaling pathway that appears to mediate this effect.
The extracellular signal-related kinase (ERK) cascade is broadly associated with regulation of cell growth and proliferation. Russell and Lane found that the components of the ERK pathway are hyperactivated in KEB-7 cells relative to their wild-type counterparts. As a result of this modified signaling activity, the apoptosis-inducing protein BAD is markedly inhibited, favoring cell survival in mutant cells.
Importantly, reduced expression of mutant K14 countered these effects in KEB-7 cells, supporting direct cross-talk between the keratin network and the ERK pathway. “This shows that the intermediate filaments are not simply a structural scaffold, but that alterations in this network can have other effects on cells, such as reducing apoptosis,” says Russell.
The keratin mutations involved in EBS lead to the formation of irregular protein ‘clumps’ within cells, similar to those observed in diseases such as Parkinson’s or Alzheimer’s, and the investigators hypothesize that this aggregation may be the cause of the apoptotic disruption observed here. These findings could lead to new insights into the pathological effects of mutant protein expression, but may also yield direct benefits for cancer research. “Severe EBS patients have a higher incidence of basal cell carcinoma,” says Russell, “and [these data] suggest that keratin could in effect be an oncogene.”
The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology.
