Deubiquitinating enzyme MINDY2 regulates TNF-α-induced cell death by targeting RIPK1

Ubiquitination plays a crucial role in the tumor necrosis factor (TNF)-α signaling pathway. To identify mechanisms by which ubiquitination regulates TNF-α signaling, we perform a screen using a gene expression library of ubiquitination-modifying enzymes. We find that the deubiquitinating enzyme MINDY2 inhibits TNF-α-induced cell death. MINDY2 modulates ubiquitination at the K612 site of RIPK1, which in turn attenuates RIPK1 recruitment by TNFR1, thereby influencing the complex 1 signaling pathway and RIPK1-dependent cell death. To investigate the in vivo function of MINDY2, we generate MINDY2-knockout mice. Compared to wild-type mice, MINDY2-deficient mice exhibit more severe hypothermia, mortality, and intestinal damage after TNF-α challenge. Collectively, our work reveals that MINDY2 is a checkpoint in RIPK1-dependent cell death, and that its deficiency exacerbates TNF-mediated tissue damage in vivo.