@article {69327, title = {Development of a First-in-Class RIPK1 Degrader to Enhance Antitumor Immunity}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Dec 16}, pages = {10683}, abstract = {

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy.

}, doi = {10.1038/s41467-024-55006-2}, url = {https://doi.org/10.1038/s41467-024-55006-2}, author = {Xin Yu and Dong Lu and Xiaoli Qi and Hanfeng Lin and Bryan L. Holloman and Feng Jin and Longyong Xu and Lang Ding and Weiyi Peng and Meng C. Wang and Xi Chen and Jin Wang} } @article {68696, title = {Mitochondrial GTP Metabolism Regulates Reproductive Aging}, journal = {bioRxiv}, year = {2023}, month = {2023 Apr 03}, abstract = {

Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS), promotes reproductive longevity in\ Caenorhabditis elegans.\ We further revealed an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by the GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mitochondrial GTP and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mitochondrial GTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and reveal mitochondrial fission induction as an effective strategy to improve reproductive health.

}, doi = {10.1101/2023.04.02.535296}, url = {https://doi.org/10.1101/2023.04.02.535296}, author = {Yi-Tang Lee and Marzia Savini and Tao Chen and Jin Yang and Qian Zhao and Lang Ding and Shihong Max Gao and Mumine Senturk and Jessica Sowa and Jue D. Wang and Meng C. Wang} }