Loss Of Conserved Gsdma3 Self-Regulation Causes Autophagy And Cell Death

GSDM family is a novel gene family containing conserved N-terminal and C terminal domains.There are four human homologs in the family:GASDERMIN A(GSDMA),GASDERMIN B(GSDMB),GASDERMIN C(GSDMC),and GASDERMIN D(GSDMD).There are no functional motif have been identified in GSDM family proteins,such as nucleus localization,transmembrane and DNA-binding motifs.The current understanding of GSDM family mainly limit to Gsdma3 mutation induced alopecia,but the physiological and biochemical function of Gsdma3 is still unclear.Gsdermin A3(Gsdma3)was originally identified as a novel hair-loss gene,mutants in which lead to skin diseases.Several missense mutations have been found,most of them occurring in the C terminus.Our study was based on an ENU-induced dominant mutant strain,Alopecia and Excoriation(AE),in which a Y to H substitution of amino acid 344 in the Gsdma3 protein sequence caused hair loss.Interestingly,we found that the newly generated null mutant of Gsdma3 mice did not display the skin morphology of AE mutants,indicating that the Gsdma3 Y344H mutation was a gain-of-function mutation.The normal skin phenotype also suggests that Gsdma3 is not essential for differentiation of epidermal cells and maintenance of the hair cycle.We studied the function of Gsdma3 in vitro and found out that the AE mutant induced autophagy.The Gsdma3 N-terminal domain alone also could induce autophagy,whereas the wild-type C-terminal domain could bind to the N-terminal domain and block pro-autophagic activity.This pro-autophagic function was associated with mitochondria and ROS generation.Other members of the GSDM family shared the conversed mechanism and performed similar functions.In conclusion,we have found that the N-terminal domain of Gsdma3 showed strong pro-autophagic activity in vivo and in vitro,and that the C terminus,as a regulator domain,could inhibit the function of the N-terminal domain.This self-regulation mechanism was conserved in the GSDM family.Our study advances the understanding of the GSDM family and hints at its physiological function GSDM.