CryoSeek identification of glycofibrils with diverse compositions and structural assemblies Li et al. report cryo-EM structures of five previously uncharacterized glycofibrils using the CryoSeek strategy, revealing diverse compositions and organizational features. Notably, TLP-0 is a glycan-only fibril. Structural analyses demonstrate that glycan-mediated interactions are essential for glycofibril assembly, highlighting the critical structural roles of glycans in these unique biomolecular architectures.

Online now! Online now! CryoSeek identification of glycofibrils with diverse compositions and structural assemblies #chembiol

Structural insights into inhibition mechanism of the helicase-primase complex from human herpesvirus 1 Sato et al. determine high resolution structures of the human herpesvirus 1 helicase primase complex (HPC), revealing how clinical inhibitors allosterically inactivate the HPC. Their findings illuminate α-subfamily drug specificity and offer a structural basis for developing antivirals targeting a wider range of herpesviruses.

Structural insights into inhibition mechanism of the helicase-primase complex from human herpesvirus 1 #chembiol

Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress Ekvik et al. genetically introduced an exogenous ATP-consuming enzyme into human cells in order to study the direct effects of energy stress in vivo. This genetic approach offers flexibility and specificity inaccessible through conventional drug-based models of energy stress. The intervention produced well-established as well as unexplored energy stress responses.

Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress #chembiol

Assessing the suitability of deubiquitylases as substrates for targeted protein degradation Tong et al. describe a chemical genetic system to evaluate the degradability of deubiquitylase (DUBs) enzymes by PROTACs that do not inhibit their catalytic activity. They find that some Dubs are readily degradable, others resist degradation through auto-deubiquitylation, and some are inherently poor proteasome substrates because they are difficult to unfold.

Assessing the suitability of deubiquitylases as substrates for targeted protein degradation

IAP-based biodegraders can convert necroptosis to apoptosis and eliminate cancer driving protein complexes Strategies that selectively degrade pathogenic proteins are gaining traction as transformative therapeutic modalities. Here, Xiuquan Ma et al. report the development of a modular protein biodegrader platform that can be programmed to convert necrotic cell death to apoptosis, concurrently eliminate multiple proto-oncogenic drivers, and uncover targetable cancer cell vulnerabilities.

IAP-based biodegraders can convert necroptosis to apoptosis and eliminate cancer driving protein complexes

Directed evolution of APOX for proximity labeling using phenols with high redox potentials The APEX2-biotin phenol proximity labeling (PL) system is a powerful tool for spatially resolved proteomics, but the spatial resolution is limited. Nitrophenols could improve spatial resolution, but APEX2 cannot perform PL using nitrophenols. Fang et al. perform directed evolution to develop APOX, enabling live-cell PL using nitrophenol probes.

Directed evolution of APOX for proximity labeling using phenols with high redox potentials

A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway By elucidating the lysosomal sorting mechanism of extracellular vesicles, Tong et al. developed a nature-inspired nanoplatform for targeted protein degradation. Featuring a modular design with multiple engineerable epitopes, the platform supports both plug-and-play antibody conjugation for individual targets and simultaneous degradation of multiple proteins via multiplexed antibody display.

A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway

Receptor-ubiquitination-targeting antibody-drug conjugates for enhanced endocytosis and lysosomal delivery Zhuang et al. address limited antibody-drug conjugates (ADCs) internalization by developing ubitaADCs that harness receptor ubiquitination. By engaging membrane E3 ligases, ubitaADCs promote receptor endocytosis and lysosomal trafficking, enhancing intracellular payload delivery and supporting a modular strategy applicable to multiple tumor-associated receptors.

Receptor-ubiquitination-targeting antibody-drug conjugates for enhanced endocytosis and lysosomal delivery

Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths PolyQ expansion drives pathological heterogeneity in Huntington’s disease. Kim et al. show polyQ103 evades p62 recognition, while bulky polyQ-p62 complexes hinder autophagosome maturation. They also demonstrate that optineurin selectively promotes autophagic clearance of K63-ubiquitinated Q103 aggregates, suggesting a polyQ length-dependent therapeutic strategy.

Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths

Lysosome-targeting chimeras enable targeted protein degradation Bozhao Li et al. review lysosome-targeting chimeras (LYTACs) as a transformative strategy for degrading extracellular and membrane proteins. They outline receptor-guided design principles, endocytic routing mechanisms, and translational challenges, highlighting how LYTACs expand targeted protein degradation beyond the proteasome.

Lysosome-targeting chimeras enable targeted protein degradation

Membrane lipids regulate the STING pathway and type I interferon responses The membrane lipid environment orchestrates stimulator of interferon genes (STING) signalosome assembly and downstream inflammatory responses. In two articles recently published in Nature, Li et al. and Tan et al. show that phosphoinositides and cholesterol cooperate to support canonical and non-canonical STING functions by potentiating agonist-dependent activation through oligomerization and trafficking. This level of regulation of STING activation highlights the crucial role of lipids in innate immune signaling.

Membrane lipids regulate the STING pathway and type I interferon responses

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins In this study, Gustafsen et al. introduce SORTACs, a PROTAC-like strategy that hijacks the sortilin-progranulin pathway to drive lysosomal degradation of extracellular proteins. SORTACs enable modular, small molecule and biologic degraders, expanding targeted protein degradation beyond the cytosol to previously inaccessible extracellular targets.

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Sorting out extracellular proteins: SORTACs harness sortilin for targeted protein degradation

Sorting out extracellular proteins: SORTACs harness sortilin for targeted protein degradation

Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression Liao et al. developed a compound that selectively degrades TBK1, a kinase playing critical roles in kidney tumorigenesis. By destroying the protein rather than just blocking its activity, this approach inhibits kidney cancer progression efficiently and uncovers new mechanistic insights into TBK1-dependent oncogenic signaling.

Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression

Degrading TBK1 to disarm VHL-deficient renal cancer Clear cell renal cell carcinoma (ccRCC) with von Hippel-Lindau (VHL) loss exhibits TBK1 dependency, and targeted therapeutic strategies outside of HIF-2α inhibition have remained limited. In this issue of Cell Chemical Biology, Liao et al. describe a second-generation cereblon-recruiting TBK1 proteolytic targeting chimera (PROTAC) with promising pre-clinical activity.

Degrading TBK1 to disarm VHL-deficient renal cancer

April issue cover of Cell Chemical Biology showing LYTAC molecules degrading target proteins

The April issue of Cell Chemical Biology is now live: A Focus Issue on Proximity-driven discovery.

Explore how induced proximity strategies are transforming the way we study biology and develop new therapeutic approaches.

Read the latest research, reviews, and perspectives.

Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression Liao et al. developed a compound that selectively degrades TBK1, a kinase playing critical roles in kidney tumorigenesis. By destroying the protein rather than just blocking its activity, this approach inhibits kidney cancer progression efficiently and uncovers new mechanistic insights into TBK1-dependent oncogenic signaling.

Online now! Online now! Selective degradation of TBK1 uncovers mechanistic insights into blocking ccRCC progression #chembiol

Directed evolution of APOX for proximity labeling using phenols with high redox potentials The APEX2-biotin phenol proximity labeling (PL) system is a powerful tool for spatially resolved proteomics, but the spatial resolution is limited. Nitrophenols could improve spatial resolution, but APEX2 cannot perform PL using nitrophenols. Fang et al. perform directed evolution to develop APOX, enabling live-cell PL using nitrophenol probes.

Online now! Online now! Directed evolution of APOX for proximity labeling using phenols with high redox potentials #chembiol

Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths PolyQ expansion drives pathological heterogeneity in Huntington’s disease. Kim et al. show polyQ103 evades p62 recognition, while bulky polyQ-p62 complexes hinder autophagosome maturation. They also demonstrate that optineurin selectively promotes autophagic clearance of K63-ubiquitinated Q103 aggregates, suggesting a polyQ length-dependent therapeutic strategy.

Online now! Online now! Distinct autophagy impairment mechanisms of huntingtin aggregates with different polyQ lengths #chembiol

A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway By elucidating the lysosomal sorting mechanism of extracellular vesicles, Tong et al. developed a nature-inspired nanoplatform for targeted protein degradation. Featuring a modular design with multiple engineerable epitopes, the platform supports both plug-and-play antibody conjugation for individual targets and simultaneous degradation of multiple proteins via multiplexed antibody display.

Online now! Online now! A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway #chembiol

Assessing the suitability of deubiquitylases as substrates for targeted protein degradation Tong et al. describe a chemical genetic system to evaluate the degradability of deubiquitylase (DUBs) enzymes by PROTACs that do not inhibit their catalytic activity. They find that some Dubs are readily degradable, others resist degradation through auto-deubiquitylation, and some are inherently poor proteasome substrates because they are difficult to unfold.

Online now! Online now! Assessing the suitability of deubiquitylases as substrates for targeted protein degradation #chembiol

Our Editor-in-Chief, Mishtu Dey, is in Suzhou, China for the Cold Spring Harbor Asia meeting: Ubiquitin Family, Autophagy and Diseases. If you’re attending, find her and share your latest research!

IAP-based biodegraders can convert necroptosis to apoptosis and eliminate cancer driving protein complexes Strategies that selectively degrade pathogenic proteins are gaining traction as transformative therapeutic modalities. Here, Xiuquan Ma et al. report the development of a modular protein biodegrader platform that can be programmed to convert necrotic cell death to apoptosis, concurrently eliminate multiple proto-oncogenic drivers, and uncover targetable cancer cell vulnerabilities.

Online now! Online now! IAP-based biodegraders can convert necroptosis to apoptosis and eliminate cancer driving protein complexes #chembiol

ER-localized ceramide accumulation contributes to replicative senescence Chitkara et al. propose a mechanistic link between disrupted ceramide trafficking and replicative senescence. Chitkara et al. demonstrate that impaired ceramide transport can lead to ER-localized ceramide accumulation, promoting ER stress and senescence. These findings establish ceramide metabolism trafficking as a key regulatory axis in replicative senescence.

Online now! Online now! ER-localized ceramide accumulation contributes to replicative senescence #chembiol

Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins In this study, Gustafsen et al. introduce SORTACs, a PROTAC-like strategy that hijacks the sortilin-progranulin pathway to drive lysosomal degradation of extracellular proteins. SORTACs enable modular, small molecule and biologic degraders, expanding targeted protein degradation beyond the cytosol to previously inaccessible extracellular targets.

Online now! Online now! Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins #chembiol

Too much of a good thing: Promotion of tumor progression and metastasis by apoptotic cells Most tumor therapies induce the apoptotic pathway in tumor and bystander cells, but apoptotic cells may paradoxically enhance tumor growth and metastasis. Hagan et al. consider the tumor-promoting effects of apoptotic cells and discuss approaches to overcome these effects.

Online now! Online now! Too much of a good thing: Promotion of tumor progression and metastasis by apoptotic cells #chembiol

Receptor-ubiquitination-targeting antibody-drug conjugates for enhanced endocytosis and lysosomal delivery Zhuang et al. address limited antibody-drug conjugates (ADCs) internalization by developing ubitaADCs that harness receptor ubiquitination. By engaging membrane E3 ligases, ubitaADCs promote receptor endocytosis and lysosomal trafficking, enhancing intracellular payload delivery and supporting a modular strategy applicable to multiple tumor-associated receptors.

Online now! Online now! Receptor-ubiquitination-targeting antibody-drug conjugates for enhanced endocytosis and lysosomal delivery #chembiol

Engineered pistol ribozymes selectively target KRAS G12V with enhanced efficacy by capping modification Liu et al. engineer a catalytic pistol ribozyme that selectively targets the KRAS p.G12V mutant transcript. By tuning ribozyme–substrate recognition and introducing a 5′ capping strategy, the authors achieve sustained and allele-specific KRAS silencing, highlighting programmable ribozymes as a precise RNA-targeting modality for oncogenic mutations.

Online now! Online now! Engineered pistol ribozymes selectively target KRAS G12V with enhanced efficacy by capping modification #chembiol

Control of the signaling of RAS proteins by modulating their palmitoylation Zhu et al. report an approach to reversibly control protein S-palmitoylation by fusing the depalmitoylase APT1 to target proteins. Using RAS proteins, they show that this approach enables the dynamic modulation of RAS palmitoylation and membrane localization by an APT1 inhibitor, and offers a platform for screening RAS palmitoyltransferase inhibitors.

Online now! Online now! Control of the signaling of RAS proteins by modulating their palmitoylation #chembiol