The autophagy protein RUBCNL/PACER represses RIPK1 kinase-dependent apoptosis and necroptosis

• DOI: 10.1080/15548627.2024.2367923
• Publication Date: 2024-06-14T10:15:35Z
• Authors: Diego Rojas-Rivera; Sebastián Beltrán; Francisco Muñoz-C...; Pablo Ahumada-Mon...; Lorena Abarzúa; Laura Gomez; Fernanda Hernandez; Cristian A. Bergmann; Luis Labrador; Melissa Calegaro-...; Mathieu J.M. Bert...; Patricio A. Manque; Ute Woehlbier
• Keywords: RIPK1; Proinflammatory cytokine

Mesenchymal stem cells (MSCs) are used in cell therapy; nonetheless, their application is limited by poor survival after transplantation a proinflammatory microenvironment. Macroautophagy/autophagy activation MSCs constitutes stress adaptation pathway, promoting cellular homeostasis. Our proteomics data indicate that RUBCNL/PACER (RUN and cysteine rich domain containing beclin 1 interacting protein like), positive regulator of autophagy, also involved death. Hence, we screened MSC upon various death stimuli under loss or gain function RUBCNL. were protected from TNF (tumor necrosis factor)-induced regulated when RUBCNL was expressed. promotes inflammation inducing RIPK1 kinase-dependent apoptosis necroptosis. We determine succumb to sensing necroptosis caspases inactivated. show negative both RIPK1-dependent Furthermore, mutants lose the ability regulate retain negatively regulating found forms complex with RIPK1, which disassembles response TNF. In line this finding, expression limits assembly RIPK1-TNFRSF1A/TNFR1 I, suggesting formation between represses signaling. These results provide new insights into crosstalk RIPK1-mediated autophagy machineries suggest RUBCNL, due its functional duality apoptosis/necroptosis, could be targeted improve therapeutic efficacy MSCs.