@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 {68531, title = {Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity}, journal = {eLife}, year = {2024}, month = {2024 Jan 19}, abstract = {

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins enriched at lysosomes mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked with longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using large-scale proteomic profiling, we systemically profiled lysosome- enriched proteomes in association with different longevity mechanisms. We further discovered the lysosomal recruitment of AMPK and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we discovered lysosomal heterogeneity across tissues as well as the specific enrichment of the Ragulator complex on Cystinosin positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity at different levels and provides resources for understanding the contribution of lysosomal proteome dynamics in modulating signal transduction, organelle crosstalk and organism longevity.

}, doi = {10.7554/eLife.85214}, url = {https://doi.org/10.7554/eLife.85214}, author = {Yong Yu and Shihong M. Gao and Youchen Guan and Pei-Wen Hu and Qinghao Zhang and Jiaming Liu and Bentian Jing and Qian Zhao and David M Sabatini and Monther Abu-Remaileh and Sung Yun Jung and Meng C. 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} }