Abstract
Mutations in Connexin-31 (Cx31) are associated with multiple human diseases including erythrokeratodermia variabilis (EKV). The molecular action of Cx31 pathogenic mutants remains largely elusive. We report here that expression of EKV pathogenic mutant Cx31R42P induces cell death with necrotic characteristics. Inhibition of hemichannel activity by a connexin hemichannel inhibitor or high extracellular calcium suppresses Cx31R42P-induced cell death. Expression of Cx31R42P induces ER stress resulting in reactive oxygen species (ROS) production, in turn, to regulate gating of Cx31R42P hemichannels and Cx31R42P induced cell death. Moreover, Cx31R42P hemichannels play an important role in mediating ATP release from the cell. In contrast, no hemichannel activity was detected with cells expressing wildtype Cx31. Together, the results suggest that Cx31R42P forms constitutively active hemichannels to promote necrotic cell death. The Cx31R42P active hemichannels are likely resulted by an ER stress mediated ROS overproduction. The study identifies a mechanism of EKV pathogenesis induced by a Cx31 mutant and provides a new avenue for potential treatment strategy of the disease.
Highlights
Connexins form gap junction channels between adjacent cells to mediate direct exchange of small cytoplasmic molecules and metabolites less than 1KD
Excessive hemichannel opening is considered to be responsible for cell death induced by Keratitis-ichthyosis-deafness syndrome (KIDS) associated Cx26 mutants [7,8,9,10], hidrotic ectodermal dysplasia (HED) related Cx30 mutants [11] and X-linked Charcot-MarieTooth (CMTX) associated Cx32 mutants [12]
Expression of Cx31R42P induces necrotic cell death We have recently found that erythrokeratodermia variabilis (EKV) pathogenic Cx31 mutants are temperature sensitive mutants
Summary
Connexins form gap junction channels between adjacent cells to mediate direct exchange of small cytoplasmic molecules and metabolites less than 1KD. They can form hemichannels on unopposed plasma membrane and allow the passage of small molecules, such as ATP and glutamine [1,2]. EKV is a rare hereditary skin disease characterized by fixed hyperkeratotic plaques and transient erythema [14,20] Both EKV and hearing loss associated mutations can induce ER stress when they are transiently expressed in cells [19,21]. The potential mechanism for Cx31R42P promoting cell death is that the mutant protein induces ER stress resulting in overproduction of reactive oxygen species (ROS). Excessive ROS promote Cx31R42P hemichannels opening, leading to cell death
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call