TY - JOUR
T1 - Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase-AIF pathway
AU - U, Kin Pong
AU - Subramanian, Venkataraman
AU - Nicholas, Antony P.
AU - Thompson, Paul R.
AU - Ferretti, Patrizia
N1 - Funding Information:
This work was supported by grants from the Child Research Appeal Trust (grant 08DB04 to PF), the Biotechnology and Biological Sciences Research Council (PF) and the National Institutes of Health (grant GM079357 to PRT). The human embryonic and fetal material was provided by the Human Developmental Biology Resource ( http://hdbr.org ) jointly funded by the Medical Research Council (grant G070089 ) and The Wellcome Trust (grant GR082557 ). We are grateful to J. Ham, JP Brockes and JC Sowden for reading the manuscript. The authors declare no competing financial interests.
PY - 2014/6
Y1 - 2014/6
N2 - PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly and association of PAD3 with vimentin, that we show to be associated also with AIF; together this suggests that PAD-dependent cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved.
AB - PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly and association of PAD3 with vimentin, that we show to be associated also with AIF; together this suggests that PAD-dependent cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved.
KW - Apoptosis inducing factor (AIF)
KW - Cell death
KW - Citrullination-deimination
KW - Human neural stem cell
KW - Peptidylarginine deiminase (PAD, PADI)
KW - Vimentin
UR - http://www.scopus.com/inward/record.url?scp=84896302174&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2014.02.018
DO - 10.1016/j.bbamcr.2014.02.018
M3 - Article
C2 - 24607566
AN - SCOPUS:84896302174
SN - 0167-4889
VL - 1843
SP - 1162
EP - 1171
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 6
ER -