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Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 uncharted aminophilic chemotypes that greatly expands the content of ligandable lysines in human proteins. Aminophilic electrophiles showed disparate proteomic reactivities that range from selective interactions with a handful of lysines to, for a set of dicarboxaldehyde fragments, remarkably broad engagement of the covalent small-molecule–lysine interactions captured by the entire library. We used these latter ‘scout’ electrophiles to efficiently map ligandable lysines in primary human immune cells under stimulatory conditions. Finally, we show that aminophilic compounds perturb diverse biochemical functions through site-selective modification of lysines in proteins, including protein–RNA interactions implicated in innate immune responses. These findings support the broad potential of covalent chemistry for targeting functional lysines in the human proteome.A deep chemical proteomic investigation of diverse aminophilic electrophiles has identified ligandable lysines across a wide range of human proteins. The proteins cover different functional and structural classes, and the aminophilic electrophiles include compounds that disrupt protein–protein and protein–RNA interactions. This dataset provides a proteome-wide atlas of lysine-reactive chemistry.

Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, however, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy that leverages broadly reactive, cysteine-directed electrophilic fragments coupled to selective ligands for intracellular proteins (for example, SLF for FKBP12, JQ1 for BRD4) to screen for heterobifunctional degrader compounds (or proteolysis targeting chimeras, PROTACs) that operate by covalent adduction of E3 ligases. This approach identified DCAF16—a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases—as a target of electrophilic PROTACs that promote the nuclear-restricted degradation of proteins. We find that only a modest fraction (~10–40%) of DCAF16 needs to be modified to support protein degradation, pointing to the potential for electrophilic PROTACs to induce neosubstrate degradation without substantially perturbing the function of the participating E3 ligase. A chemical proteomics strategy identifies DCAF16 as a potential ubiquitin ligase recruiter for cysteine-directed electrophilic PROTACs to promote the degradation of nuclear proteins.

The heat shock protein 90 (Hsp90) family of molecular chaperones regulates protein homeostasis, folding, and degradation. The ER-resident Hsp90 isoform, glucose-regulated protein 94 (Grp94), promotes the aggregation of mutant forms of myocilin, a protein associated with primary open-angle glaucoma. While inhibition of Grp94 promotes the degradation of mutant myocilin in vitro , to date no Grp94-selective inhibitors have been investigated in vivo . Here, a Grp94-selective inhibitor facilitated mutant myocilin degradation and rescued phenotypes in a transgenic mouse model of hereditary primary open-angle glaucoma. Ocular toxicities previously associated with pan-Hsp90 inhibitors were not evident with our Grp94-selective inhibitor, 4-Br-BnIm. Our study suggests that selective inhibition of a distinct Hsp90 family member holds translational promise for ocular and other diseases associated with cell stress and protein misfolding.

Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy to discover that DCAF16 - a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases - promotes nuclear-restricted protein degradation upon modification by cysteine-directed heterobifunctional electrophilic compounds.

Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving direct functional perturbation and/or ligand-induced degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells, underscoring the potential of electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.

Neoadjuvant use of immune checkpoint inhibitors (ICIs) before liver resection results in pathological tumour regression in patients with hepatocellular carcinoma. We aimed to describe the characteristics of pathological responses after preoperative ICI therapy for hepatocellular carcinoma and to evaluate the association between the depth of tumour regression and relapse-free survival. In this cross-trial, patient-level analysis, we performed a pooled analysis of data from patients with hepatocellular carcinoma receiving ICI therapy before liver resection as part of a global collaborative consortium (NeoHCC) of five phase 1 and 2 clinical trials and standardised observational protocols conducted in 12 tertiary referral centres across the USA, UK, and Taiwan. Eligible patients were adults (aged ≥18 years) diagnosed with hepatocellular carcinoma by tissue core biopsy before treatment initiation, a Liver Imaging Reporting and Data System score of 5 on imaging, or both, with an Eastern Cooperative Oncology Group performance status score of 0–1, and no extrahepatic spread or previous ICI treatment. Pathological response was measured as the percentage of non-viable tumour in the resected surgical specimen, with major pathological response corresponding to at least 70% tumour regression and pathological complete response corresponding to 100% tumour regression. We correlated pathological response with radiological overall response using RECIST criteria (version 1.1) and relapse-free survival, and evaluated the threshold of tumour regression that could be optimally associated with relapse-free survival. At data cutoff on Jan 31, 2024, 111 patients were included in the study, of whom data on pathological response were available for 104 (94%) patients. Patients received treatment from Oct 5, 2017, to Nov 15, 2023, mostly ICI combinations (76 [69%]), for a median of 1·4 months (IQR 0·7–2·9). 87 (78%) patients were men and 24 (22%) were women. Most patients had underlying viral chronic liver disease (73 [66%]) and Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma (61 [55%]), without portal vein thrombosis (87 [78%]). We observed major pathological response in 33 (32%) patients and pathological complete response in 19 (18%) patients. Radiological overall response was associated with major pathological response, with 23 (74%) of 31 patients with radiological response showing major pathological response compared with ten (14%) of 73 patients without radiological response (p<0·0001). However, ten (30%) of 33 major pathological responses were not predicted by radiological response. After a median follow-up of 27·2 months (95% CI 22·3–32·1), median relapse-free survival for the whole cohort was 43·6 months (95% CI 28·3–not evaluable). Relapse-free survival was significantly longer in patients with major pathological response than in those who did not have a major pathological response (not reached [95% CI not evaluable–not evaluable] vs 28·3 months [12·8–43·8]; hazard ratio 0·26 [0·10–0·66]; p=0·0024) and in patients with pathological complete response than in those who did not have a pathological complete response (NR [95% CI not evaluable–not evaluable] vs 32·8 months [15·0–50·5]; 0·19 [0·05–0·78]; p=0·010). Unbiased recursive partitioning of the cohort for the risk of relapse, death, or both identified a threshold of 90% as the optimal cutoff of pathological tumour regression to predict improved relapse-free survival. The extent of tumour regression following neoadjuvant ICI therapy could identify patients with improved relapse-free survival following liver resection. The threshold of at least 90% tumour regression should be validated for its surrogate role for relapse-free survival in phase 3 randomised controlled trials. None.

In the past two decades, three coronaviruses with ancestral origins in bats have emerged and caused widespread outbreaks in humans, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first SARS epidemic in 2002–2003, the appreciation of bats as key hosts of zoonotic coronaviruses has advanced rapidly. More than 4,000 coronavirus sequences from 14 bat families have been identified, yet the true diversity of bat coronaviruses is probably much greater. Given that bats are the likely evolutionary source for several human coronaviruses, including strains that cause mild upper respiratory tract disease, their role in historic and future pandemics requires ongoing investigation. We review and integrate information on bat–coronavirus interactions at the molecular, tissue, host and population levels. We identify critical gaps in knowledge of bat coronaviruses, which relate to spillover and pandemic risk, including the pathways to zoonotic spillover, the infection dynamics within bat reservoir hosts, the role of prior adaptation in intermediate hosts for zoonotic transmission and the viral genotypes or traits that predict zoonotic capacity and pandemic potential. Filling these knowledge gaps may help prevent the next pandemic.Bats harbour a multitude of coronaviruses and owing to their diversity and wide distribution are prime reservoir hosts of emerging viruses. Ruiz-Aravena, McKee and colleagues analyse the currently available information on bat coronaviruses and discuss their role in recent and potential future spillovers.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin‐releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 ( FGFR1 ) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β‐Klotho (KLB), the obligate co‐receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH. Genetic screening of 334 CHH patients identified seven heterozygous loss‐of‐function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction. Synopsis Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction. Heterozygous loss‐of‐function mutations in KLB are found in patients with congenital hypogonadotropic hypogonadism. Klb ‐deficient mice delayed sexual maturation and impaired fertility with decreased gonadotropins due to a hypothalamic defect. Klb is expressed in the postnatal hypothalamus including GnRH neurons. FGF21 reaches GnRH neurons via fenestrated capillaries in the hypothalamus in vivo and enhances GnRH release in median eminence explants in vitro . Graphical Abstract Defects in FGF21/KLB/FGFR1 signaling contribute to GnRH deficiency in both humans and mice. This signaling pathway is a novel link between metabolism and reproduction.

We present direct measurements of biogenic volatile organic compound (BVOC)-induced nitrate radical (NO3) reactivity (kVOC) through the diel cycle in the suburban, temperate forest of Rambouillet near Paris (France). The data were obtained in a 6-week summer period in 2022 as part of the Atmospheric ChemistRy Of the Suburban foreSt (ACROSS) campaign. kVOC was measured in a small (700 m2) clearing mainly at a height of 5.5 m above ground level but also at 40 m (for 5 d and nights). At nighttime, mean values (and 25th–75th percentile ranges) of knightVOC(5.5m) = (0.24-0.06+0.32) s-1 and knightVOC(40m) = (0.016-0.007+0.018) s-1 indicate a significant vertical gradient and low NO3 reactivity above the canopy, whereas knightVOC(5.5 m) showed peak values of up to 2 s-1 close to the ground. The strong vertical gradient in NO3 reactivity could be confirmed by measurements between 0 and 24 m on one particular night characterized by a strong temperature inversion and is a result of the decoupling of air masses aloft from the ground- and canopy-level sources of BVOCs (and nitric oxide, NO). No strong vertical gradient was observed in the mean daytime NO3 reactivity, with kdayVOC(5.5m) = (0.12±0.04) s-1 for the entire campaign and kdayVOC(40m) = (0.07±0.02) s-1 during the 5 d period.Within the clearing, the fractional contribution of VOCs to the total NO3 loss rate coefficient (ktot, determined by photolysis, reaction with NO and VOCs) was 80 %–90 % during the night and ∼ 50 % during the day. In terms of chemical losses of α-pinene below canopy height in the clearing, we find that at nighttime hydroxyl radicals (OH) and ozone (O3) dominate, with NO3 contributing “only” 17 %, which decreases further to 8.5 % during the day. Based on measured OH, measured O3, and calculated NO3 concentrations, the chemical lifetime of BVOCs at noon is about 1 h and is likely to be longer than timescales of transport out of the canopy (typically of the order of minutes), thus significantly reducing the importance of daytime in-canopy processing. Clearly, in forested regions where sufficient nitric oxide and nitrogen dioxide (NOx) is available, the role of NO3 and OH as initiators of BVOC oxidation is not strictly limited to nighttime and daytime, respectively, as often implied in e.g. atmospheric chemistry textbooks.