The immunosuppressor mycophenolic acid kills activated lymphocytes by inducing a nonclassical actin-dependent necrotic signal.
Mycophenolate mofetil (MMF) is an immunosuppressive agent used in transplantation. Over the last decade, MMF has also emerged as an alternative therapeutic regimen for autoimmune diseases, mainly for patients refractory to other therapies. The active compound of MMF, mycophenolic acid (MPA), depletes the intracellular pool of guanosine tri-phosphate through inosine monophosphate dehydrogenase blockade. The molecular mechanism involved in the elimination of T and B lymphocytes upon inhibition of inosine monophosphate dehydrogenase remains elusive. In this study, we showed that in contrast to the immunosuppressors azathioprine, cyclosporin A, and tacrolimus, MPA killed lymphocytes through the activation of a caspase-independent necrotic signal. Furthermore, the MPA-mediated necrotic signal relied on the transmission of a novel intracellular signal involving Rho-GTPase Cdc42 activity and actin polymerization. In addition to its medical interest, this study sheds light on a novel and atypical molecular mechanism leading to necrotic cell death.
Chaigne-Delalande
Benjamin
B
Université de Bordeaux-2, Bordeaux, France.
Guidicelli
Gwendaline
G
Couzi
Lionel
L
Merville
Pierre
P
Mahfouf
Walid
W
Bouchet
Stéphane
S
Molimard
Mathieu
M
Pinson
Benoit
B
Moreau
Jean-François
JF
Legembre
Patrick
P
D000199:Actins / Q000276:immunology* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006160:Guanosine Triphosphate / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000276:immunology / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D009336:Necrosis / Q000139:chemically induced / Q000276:immunology; D016377:Organ Transplantation; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D020764:cdc42 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism
D000199:Actins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D000251:Adenosine Triphosphatases; C031715:rho-ATPase; D020764:cdc42 GTP-Binding Protein; D009173:Mycophenolic Acid