Cell Chemical Biology

Online now! Online now! Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists #chembiol

Optogenetic control of biomolecular organization reveals distinct roles of phase separation in RTK signaling Zhou et al. present a light-controllable condensation system, CORdensate, which enables robust and broad activation of receptor tyrosine kinases (RTKs) through phase separation. By engineering CORdensate variants that span from monomeric to phase-separated forms, the study demonstrates the efficient organizational capacity of phase separation in cellular signaling.

Online now! Online now! Optogenetic control of biomolecular organization reveals distinct roles of phase separation in RTK signaling #chembiol

Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol Feng et al. developed an inclusion-complex-enhanced nano-micelle formulation of CBD (CBD-IN) that enhances brain delivery and rapidly suppresses neuropathic pain in mice without affecting normal function. Circuit mapping and calcium imaging reveal state-dependent suppression of pathological hyperactivity, highlighting CBD-IN as a promising therapeutic strategy.

Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol

Development of D2HG biosensors inspired by the molecular mechanism of D2HG regulation of DhdR Wang et al. engineered D2HG biosensors (DHsers) leveraging insights from structural mechanism of D2HG regulation of DhdR, achieving varying detection ranges. The DHsers enable the detection of D2HG dynamics in healthy cells and disease-relevant IDH mutant living cells, providing a valuable tool for quantifying subcellular D2HG levels.

Development of D2HG biosensors inspired by the molecular mechanism of D2HG regulation of DhdR

An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels Abrams et al. used circular permutation to develop a reversible FRET-based cysteine sensor. Biochemical and cell-based experiments established the sensor’s sensitivity and selectivity for cysteine. High-throughput phenotypic screens identified compounds that modulate cysteine levels, establishing the sensor as a valuable tool for studying cellular cysteine regulation.

An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels

Lactylation of mTOR enhances autophagy in skeletal muscle during exercise Based on an acute exercise model, Yan et al. identify lactate as a positive regulator of autophagy in skeletal muscle. Lactate triggers muscle autophagy via K921 lactylation-dependent inactivation of mTORC1. This study establishes a mechanistic framework for understanding exercise-induced muscle adaptation, guiding treatment strategies for muscle and metabolic disorders.

Lactylation of mTOR enhances autophagy in skeletal muscle during exercise

TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics Yuan et al. identify TRIM28 as a key component of stress granules (SGs) using the lcFAX-MS approach established here and define TRIM28-mediated G3BP1/2 SUMOylation as a critical mechanism regulating SG dynamics. TRIM28’s role in regulating SGs, facilitated by lcFAX-MS, provides a promising framework for studying diverse LLPS events.

TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics

The limitations of small molecule and genetic screening in phenotypic drug discovery Phenotypic drug discovery is a powerful tool for uncovering new therapies, but small molecule and genetic screens each have distinct limitations. Vincent and Gianni analyze these challenges and suggest practical mitigation strategies to maximize screening success.

The limitations of small molecule and genetic screening in phenotypic drug discovery

STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency Loss of RNF43 leads to aberrant Wnt signaling, promoting aggressive cancers for which effective treatments are lacking. He et al. demonstrate that STT3A is critical for the survival of RNF43-deficient tumors, identifying it as a promising therapeutic target validated through both in vitro and in vivo studies.

STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency

STT3A: Finding the sugar in Wnt signaling

Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression Targeting the WDR5-MLL1 interaction offers a promising therapeutic strategy for leukemia. Zhang et al. developed Ac7, an EMBOW-derived peptide that binds WDR5 with nanomolar affinity, disrupts the WDR5-MLL1 interaction, and suppresses leukemia cell growth in vivo with relatively low toxicity.

Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression

Small proteins with a big job: An EMBOW-derived microprotein targets WDR5-MLL1 and suppresses transcription in leukemia In this issue of Cell Chemical Biology, Zhang et al. report the identification of a high-affinity EMBOW-derived inhibitor of WDR5, Ac7, which demonstrates in-cell target engagement and in vivo antileukemic efficacy. The microprotein-inspired inhibitor potently blocks the WDR5-MLL1 interaction, suppressing H3K4 methylation and transcription of target genes in mixed lineage leukemia (MLL)-rearranged leukemia.

Small proteins with a big job: An EMBOW-derived microprotein targets WDR5-MLL1 and suppresses transcription in leukemia

Meet the authors: Yi Yuan and Yaoyang Zhang In an interview with Dr. Mishtu Dey, the editor-in-chief of Cell Chemical Biology, the authors of the research article entitled “TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics” share insights about their work and reflect on their scientific field and their journeys as researchers.

Meet the authors: Yi Yuan and Yaoyang Zhang

The November issue of Cell Chemical Biology is live! Click here to read: www.cell.com/issue/S2451-...

Phytate enhances gut Parasutterella colonization to alleviate radiation injury Li et al. demonstrated that phytate confers radioprotective effects by promoting colonization of symbiotic Parasutterella, which produce the metabolites PLA and NL. These metabolites help mitigate radiation-induced intestinal injury (RIII) via M2-like macrophage polarization and antioxidant activity, highlighting phytate’s potential benefits for cancer patients undergoing radiotherapy without increasing gut burden.

Online now! Online now! Phytate enhances gut Parasutterella colonization to alleviate radiation injury #chembiol

The limitations of small molecule and genetic screening in phenotypic drug discovery Phenotypic drug discovery is a powerful tool for uncovering new therapies, but small molecule and genetic screens each have distinct limitations. Vincent and Gianni analyze these challenges and suggest practical mitigation strategies to maximize screening success.

Online now! Online now! The limitations of small molecule and genetic screening in phenotypic drug discovery #chembiol

Lactylation of mTOR enhances autophagy in skeletal muscle during exercise Based on an acute exercise model, Yan et al. identify lactate as a positive regulator of autophagy in skeletal muscle. Lactate triggers muscle autophagy via K921 lactylation-dependent inactivation of mTORC1. This study establishes a mechanistic framework for understanding exercise-induced muscle adaptation, guiding treatment strategies for muscle and metabolic disorders.

Online now! Online now! Lactylation of mTOR enhances autophagy in skeletal muscle during exercise #chembiol

An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels Abrams et al. used circular permutation to develop a reversible FRET-based cysteine sensor. Biochemical and cell-based experiments established the sensor’s sensitivity and selectivity for cysteine. High-throughput phenotypic screens identified compounds that modulate cysteine levels, establishing the sensor as a valuable tool for studying cellular cysteine regulation.

Online now! Online now! An engineered cysteine sensor optimized for high-throughput screening identifies regulators of intracellular thiol levels #chembiol

Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol Feng et al. developed an inclusion-complex-enhanced nano-micelle formulation of CBD (CBD-IN) that enhances brain delivery and rapidly suppresses neuropathic pain in mice without affecting normal function. Circuit mapping and calcium imaging reveal state-dependent suppression of pathological hyperactivity, highlighting CBD-IN as a promising therapeutic strategy.

Online now! Online now! Rapid suppression of neuropathic pain and somatosensory hyperactivity by nano-formulated cannabidiol #chembiol

Development of D2HG biosensors inspired by the molecular mechanism of D2HG regulation of DhdR Wang et al. engineered D2HG biosensors (DHsers) leveraging insights from structural mechanism of D2HG regulation of DhdR, achieving varying detection ranges. The DHsers enable the detection of D2HG dynamics in healthy cells and disease-relevant IDH mutant living cells, providing a valuable tool for quantifying subcellular D2HG levels.

Online now! Online now! Development of D2HG biosensors inspired by the molecular mechanism of D2HG regulation of DhdR #chembiol

TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics Yuan et al. identify TRIM28 as a key component of stress granules (SGs) using the lcFAX-MS approach established here and define TRIM28-mediated G3BP1/2 SUMOylation as a critical mechanism regulating SG dynamics. TRIM28’s role in regulating SGs, facilitated by lcFAX-MS, provides a promising framework for studying diverse LLPS events.

Online now! Online now! TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics #chembiol

Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression Targeting the WDR5-MLL1 interaction offers a promising therapeutic strategy for leukemia. Zhang et al. developed Ac7, an EMBOW-derived peptide that binds WDR5 with nanomolar affinity, disrupts the WDR5-MLL1 interaction, and suppresses leukemia cell growth in vivo with relatively low toxicity.

Online now! Online now! Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression #chembiol

Cover image for joint collection with title and journal names

Explore our collection w/ @cp-cellhostmicrobe.bsky.social: Molecular Mechanisms of Host-Microbiome Interactions. Discover the cross talk between microbes and their human hosts that shapes health and disease. http://dlvr.it/TNrk90

STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency Loss of RNF43 leads to aberrant Wnt signaling, promoting aggressive cancers for which effective treatments are lacking. He et al. demonstrate that STT3A is critical for the survival of RNF43-deficient tumors, identifying it as a promising therapeutic target validated through both in vitro and in vivo studies.

Online now! STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency #chembiol

Valence and avidity determine the agonistic activity of anti-TNFR2 nanobody fusion proteins http://dlvr.it/TNkwXZ

Inter- and intra-tumoral ALDH1 heterogeneity in breast cancer identifies therapeutic opportunities for ALDH1A-specific inhibitors http://dlvr.it/TNkv8p

CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity http://dlvr.it/TNksyq

Discovery of a tau-aggregate clearing compound that covalently targets P4HB http://dlvr.it/TNkrfR

Sensing within: Mitochondrial inside-out signal transduction http://dlvr.it/TNkqLD

Organelle-ly speaking: Cracking the code of cellular clean-up http://dlvr.it/TNknYf