ZFP36 stabilizes RIP1 via degradation of XIAP and cIAP2 thereby promoting ripoptosome assembly.
BACKGROUND
ZFP36 is an mRNA binding protein that exerts anti-tumor activity in glioblastoma by triggering cell death, associated to an increase in the stability of the kinase RIP1.


METHODS
We used cell death assays, size exclusion chromatography, Co-Immunoprecipitation, shRNA lentivectors and glioma neural stem cells to determine the effects of ZFP36 on the assembly of a death complex containing RIP1 and on the induction of necroptosis.


RESULTS
Here we demonstrate that ZFP36 promotes the assembly of the death complex called Ripoptosome and induces RIP1-dependent death. This involves the depletion of the ubiquitine ligases cIAP2 and XIAP and leads to the association of RIP1 to caspase-8 and FADD. Moreover, we show that ZFP36 controls RIP1 levels in glioma neural stem cell lines.


CONCLUSIONS
We provide a molecular mechanism for the tumor suppressor role of ZFP36, and the first evidence for Ripoptosome assembly following ZFP36 expression. These findings suggest that ZFP36 plays an important role in RIP1-dependent cell death in conditions where IAPs are depleted.
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. tselmi@gmail.com.
Tommaso
T
Selmi
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. claudia.alecci@gmail.com.
Claudia
C
Alecci
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. miriam.dellaquila@gmail.com.
Miriam
M
dell' Aquila
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. lucia.montorsi@unimore.it.
Lucia
L
Montorsi
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. martelloandrea@gmail.com.
Andrea
A
Martello
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. 72295@studenti.unimore.it.
Filippo
F
Guizzetti
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. nicola.volpi@unimore.it.
Nicola
N
Volpi
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. sandra.parenti@unimore.it.
Sandra
S
Parenti
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. sergio.ferrari@unimore.it.
Sergio
S
Ferrari
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6BT, United Kingdom. p.salomoni@ucl.ac.uk.
Paolo
P
Salomoni
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. alexis.grande@unimore.it.
Alexis
A
Grande
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy. zanocco@unimore.it.
Tommaso
T
Zanocco-Marani
D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D045744:Cell Line, Tumor; D004795:Enzyme Stability; D005910:Glioma / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D055503:Protein Multimerization; D059748:Proteolysis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D051816:Tristetraprolin / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; D051816:Tristetraprolin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C497552:ZFP36 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases