Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex.

Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-Gi signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and Gi coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.

Gestational Hypoxia and Developmental Plasticity.

Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed.

Differential performance of RoseTTAFold in antibody modeling.

Antibodies are essential to life, and knowing their structures can facilitate the understanding of antibody-antigen recognition mechanisms. Precise antibody structure prediction has been a core challenge for a prolonged period, especially the accuracy of H3 loop prediction. Despite recent progress, existing methods cannot achieve atomic accuracy, especially when the homologous structures required for these methods are not available. Recently, RoseTTAFold, a deep learning-based algorithm, has shown remarkable breakthroughs in predicting the 3D structures of proteins. To assess the antibody modeling ability of RoseTTAFold, we first retrieved the sequences of 30 antibodies as the test set and used RoseTTAFold to model their 3D structures. We then compared the models constructed by RoseTTAFold with those of SWISS-MODEL in a different way, in which we stratified Global Model Quality Estimate (GMQE) into three different ranges. The results indicated that RoseTTAFold could achieve results similar to SWISS-MODEL in modeling most CDR loops, especially the templates with a GMQE score under 0.8. In addition, we also compared the structures modeled by RoseTTAFold, SWISS-MODEL and ABodyBuilder. In brief, RoseTTAFold could accurately predict 3D structures of antibodies, but its accuracy was not as good as the other two methods. However, RoseTTAFold exhibited better accuracy for modeling H3 loop than ABodyBuilder and was comparable to SWISS-MODEL. Finally, we discussed the limitations and potential improvements of the current RoseTTAFold, which may help to further the accuracy of RoseTTAFold's antibody modeling.

TET2 confers a mechanistic link of microRNA-210 and mtROS in hypoxia-suppressed spontaneous transient outward currents in uterine arteries of pregnant sheep.

Hypoxia during pregnancy impairs uterine vascular adaptation via microRNA-210 (miR-210)-mediated mitochondrial dysfunction and mitochondrial reactive oxygen species (mtROS) generation. TET methylcytosine dioxygenase 2 (TET2) participates in regulating inflammation and oxidative stress and its deficiency contributes to the pathogenesis of multiple cardiovascular diseases. Thus, we hypothesize a role of TET2 in hypoxia/miR-210-mediated mtROS suppressing spontaneous transient outward currents (STOCs) in uterine arteries. We found that gestational hypoxia downregulated TET2 in uterine arteries of pregnant sheep and TET2 was a target of miR-210. Knockdown of TET2 with small interfering RNAs suppressed mitochondrial respiration, increased mtROS, inhibited STOCs and elevated myogenic tone. By contrast, overexpression of TET2 negated hypoxia- and miR-210-induced mtROS. The effects of TET2 knockdown in uterine arteries on mtROS, STOCs and myogenic contractions were blocked by the mitochondria-targeted antioxidant MitoQ. In addition, the recovery effects of inhibiting endogenous miR-210 with miR-210-LNA on hypoxia-induced suppression of STOCs and augmentation of myogenic tone were reversed by TET2 knockdown in uterine arteries. Together, our study reveals a novel mechanistic link between the miR-210-TET2-mtROS pathway and inhibition of STOCs and provides new insights into the understanding of uterine vascular maladaptation in pregnancy complications associated with gestational hypoxia. KEY POINTS: Gestational hypoxia downregulates TET methylcytosine dioxygenase 2 (TET2) in uterine arteries of pregnant sheep. TET2 is a downstream target of microRNA-210 (miR-210) and miR-210 mediates hypoxia-induced TET2 downregulation. Knockdown of TET2 in uterine arteries recapitulates the effect of hypoxia and miR-210 and impairs mitochondrial bioenergetics and increases mitochondrial reactive oxygen species (mtROS) . Overexpression of TET2 negates the effect of hypoxia and miR-210 on increasing mtROS. TET2 knockdown reiterates the effect of hypoxia and miR-210 and suppresses spontaneous transient outward currents (STOCs) and elevates myogenic tone, and these effects are blocked by MitoQ. Knockdown of TET2 reverses the miR-210-LNA-induced reversal of the effects of hypoxia on STOCs and myogenic tone in uterine arteries.

MCCS, a novel characterization method for protein-ligand complex.

Delineating the fingerprint or feature vector of a receptor/protein will facilitate the structural and biological studies, as well as the rational design and development of drugs with high affinities and selectivity. However, protein is complicated by its different functional regions that can bind to some of its protein partner(s), substrate(s), orthosteric ligand(s) or allosteric modulator(s) where cogent methods like molecular fingerprints do not work well. We here elaborate a scoring-function-based computing protocol Molecular Complex Characterizing System to help characterize the binding feature of protein-ligand complexes. Based on the reported receptor-ligand interactions, we first quantitate the energy contribution of each individual residue which may be an alternative of MD-based energy decomposition. We then construct a vector for the energy contribution to represent the pattern of the ligand recognition at a receptor and qualitatively analyze the matching level with other receptors. Finally, the energy contribution vector is explored for extensive use in similarity and clustering. The present work provides a new approach to cluster proteins, a perspective counterpart for determining the protein characteristics in the binding, and an advanced screening technique where molecular docking is applicable.

Virus-CKB: an integrated bioinformatics platform and analysis resource for COVID-19 research.

Given the scale and rapid spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for medicines that can help before vaccines are available. In this study, we present a viral-associated disease-specific chemogenomics knowledgebase (Virus-CKB) and apply our computational systems pharmacology-target mapping to rapidly predict the FDA-approved drugs which can quickly progress into clinical trials to meet the urgent demand of the COVID-19 outbreak. Virus-CKB reuses the underlying platform of our DAKB-GPCRs but adds new features like multiple-compound support, multi-cavity protein support and customizable symbol display. Our one-stop computing platform describes the chemical molecules, genes and proteins involved in viral-associated diseases regulation. To date, Virus-CKB archived 65 antiviral drugs in the market, 107 viral-related targets with 189 available 3D crystal or cryo-EM structures and 2698 chemical agents reported for these target proteins. Moreover, Virus-CKB is implemented with web applications for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, NGL Viewer, Spider Plot, etc. The Virus-CKB server is accessible at https://www.cbligand.org/g/virus-ckb.

IsAb: a computational protocol for antibody design.

The design of therapeutic antibodies has attracted a large amount of attention over the years. Antibodies are widely used to treat many diseases due to their high efficiency and low risk of adverse events. However, the experimental methods of antibody design are time-consuming and expensive. Although computational antibody design techniques have had significant advances in the past years, there are still some challenges that need to be solved, such as the flexibility of antigen structure, the lack of antibody structural data and the absence of standard antibody design protocol. In the present work, we elaborated on an in silico antibody design protocol for users to easily perform computer-aided antibody design. First, the Rosetta web server will be applied to generate the 3D structure of query antibodies if there is no structural information available. Then, two-step docking will be used to identify the binding pose of an antibody-antigen complex when the binding information is unknown. ClusPro is the first method to be used to conduct the global docking, and SnugDock is applied for the local docking. Sequentially, based on the predicted binding poses, in silico alanine scanning will be used to predict the potential hotspots (or key residues). Finally, computational affinity maturation protocol will be used to modify the structure of antibodies to theoretically increase their affinity and stability, which will be further validated by the bioassays in the future. As a proof of concept, we redesigned antibody D44.1 and compared it with previously reported data in order to validate IsAb protocol. To further illustrate our proposed protocol, we used cemiplimab antibody, a PD-1 checkpoint inhibitor, as an example to showcase a step-by-step tutorial.

MCCS: a novel recognition pattern-based method for fast track discovery of anti-SARS-CoV-2 drugs.

Given the scale and rapid spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, or 2019-nCoV), there is an urgent need to identify therapeutics that are effective against COVID-19 before vaccines are available. Since the current rate of SARS-CoV-2 knowledge acquisition via traditional research methods is not sufficient to match the rapid spread of the virus, novel strategies of drug discovery for SARS-CoV-2 infection are required. Structure-based virtual screening for example relies primarily on docking scores and does not take the importance of key residues into consideration, which may lead to a significantly higher incidence rate of false-positive results. Our novel in silico approach, which overcomes these limitations, can be utilized to quickly evaluate FDA-approved drugs for repurposing and combination, as well as designing new chemical agents with therapeutic potential for COVID-19. As a result, anti-HIV or antiviral drugs (lopinavir, tenofovir disoproxil, fosamprenavir and ganciclovir), antiflu drugs (peramivir and zanamivir) and an anti-HCV drug (sofosbuvir) are predicted to bind to 3CLPro in SARS-CoV-2 with therapeutic potential for COVID-19 infection by our new protocol. In addition, we also propose three antidiabetic drugs (acarbose, glyburide and tolazamide) for the potential treatment of COVID-19. Finally, we apply our new virus chemogenomics knowledgebase platform with the integrated machine-learning computing algorithms to identify the potential drug combinations (e.g. remdesivir+chloroquine), which are congruent with ongoing clinical trials. In addition, another 10 compounds from CAS COVID-19 antiviral candidate compounds dataset are also suggested by Molecular Complex Characterizing System with potential treatment for COVID-19. Our work provides a novel strategy for the repurposing and combinations of drugs in the market and for prediction of chemical candidates with anti-COVID-19 potential.

Anisotropic Nonlocal Damping in Ferromagnet/α-GeTe Bilayers Enabled by Splitting Energy Bands.

The understanding and manipulation of anisotropic Gilbert damping is crucial for both fundamental research and versatile engineering and optimization. Although several works on anisotropic damping have been reported, no direct relationship between the band structure and anisotropic damping was established. Here, we observed an anisotropic damping in Fe/GeTe manipulated by the symmetric band structures of GeTe via angle-resolved photoemission spectroscopy. Moreover, the anisotropic damping can be modified by the symmetry of band structures. Our Letter provides insightful understandings of the anisotropic Gilbert damping in ferromagnets interfaced with Rashba semiconductors and suggests the possibility of manipulating the Gilbert damping by band engineering.

Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation.

Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is thus vital to the well-being of the mother and fetus. Ca2+-activated K+ (KCa) channels of small, intermediate, and large conductance participate in setting and regulating the resting membrane potential of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and play a critical role in controlling vascular tone and blood pressure. KCa channels are important mediators of estrogen/pregnancy-induced adaptive changes in the uteroplacental circulation. Activation of the channels hyperpolarizes uteroplacental VSMCs/ECs, leading to attenuated vascular tone, blunted vasopressor responses, and increased uteroplacental blood flow. However, the regulation of uteroplacental vascular function by KCa channels is compromised in pregnancy complications. This review intends to provide a comprehensive overview of roles of KCa channels in the regulation of the uteroplacental circulation under physiological and pathophysiological conditions.

Discovery of a pyrano[2,3-b]pyridine derivative YX-2102 as a cannabinoid receptor 2 agonist for alleviating lung fibrosis.

BACKGROUND: Pharmacological modulation of cannabinoid 2 receptor (CB2R) is a promising therapeutic strategy for pulmonary fibrosis (PF). Thus, to develop CB2R selective ligands with new chemical space has attracted much research interests. This work aims to discover a novel CB2R agonist from an in-house library, and to evaluate its therapeutic effects on PF model, as well as to disclose the pharmacological mechanism. METHODS: Virtual screening was used to identify the candidate ligand for CB2R from a newly established in-house library. Both in vivo experiments on PF rat model and in vitro experiments on cells were performed to investigate the therapeutic effects of the lead compound and underlying mechanism. RESULTS: A "natural product-like" pyrano[2,3-b]pyridine derivative, YX-2102 was identified that bound to CB2R with high affinity. Intraperitoneal YX-2102 injections significantly ameliorated lung injury, inflammation and fibrosis in a rat model of PF induced by bleomycin (BLM). On one hand, YX-2102 inhibited inflammatory response at least partially through modulating macrophages polarization thereby exerting protective effects. Whereas, on the other hand, YX-2102 significantly upregulated CB2R expression in alveolar epithelial cells in vivo. Its pretreatment inhibited lung alveolar epithelial-to-mesenchymal transition (EMT) in vitro and PF model induced by transforming growth factor beta-1 (TGF-ß1) via a CB2 receptor-dependent pathway. Further studies suggested that the Nrf2-Smad7 pathway might be involved in. CONCLUSION: These findings suggest that CB2R is a potential target for PF treatment and YX-2102 is a promising CB2R agonist with new chemical space.

Mitochondrial Dysfunction in the Pathogenesis of Preeclampsia.

PURPOSE OF REVIEW: Preeclampsia complicates 5-10% of all pregnancies and is a leading cause of maternal and perinatal mortality and morbidity. The placenta plays a pivotal role in determining pregnancy outcome by supplying the fetus with oxygen and nutrients and by synthesizing hormones. Placental function is highly dependent on energy supplied by mitochondria. It is well-known that preeclampsia is originated from placental dysfunction, although the etiology of it remains elusive. RECENT FINDINGS: During the last three decades, substantial evidence suggests that mitochondrial abnormality is a major contributor to placental dysfunction. In addition, mitochondrial damage caused by circulating bioactive factors released from the placenta may cause endothelial dysfunction and subsequent elevation in maternal blood pressure. In this review, we summarize the current knowledge of mitochondrial abnormality in the pathogenesis of preeclampsia and discuss therapeutic approaches targeting mitochondria for treatment of preeclampsia.

Characterization of complete mitochondrial genome of the common tiger, Danaus genutia (Lepidoptera: Nymphalidae: Danainae) and phylogenetic implications within the subfamily Danainae.

Nymphalidae is the most diverse butterfly family worldwide, with more than 6000 species, whereas the mitogenomic data of nymphalid species, especially the subfamily Danainae, is still lacking for more comprehensive systematic studies. To this contribution, the complete mitogenome of Danaus genutia (Lepidoptera: Nymphalidae: Danainae) was determined via sequencing and annotating. The mitogenome in total consists of 15,255 base pairs (bp), containing 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs, and a 440-bp noncoding A+T-rich region. Furthermore, phylogeny of the subfamily Danainae was reconstructed applying maximum likelihood and Bayesian inference on the basis of the mitogenomic data sets. Combined with our analysis and previous studies, the genus-level phylogenetic relationships within the subfamily Danainae are ((Tirumala + Danaus) + ((Idea + Euploea) + (Ideopsis + Parantica))). This study offers molecular information and provides a new perspective for phylogenetic research within the subfamily Danainae.

Three-Dimensional Limit of Bulk Rashba Effect in Ferroelectric Semiconductor GeTe.

Ferroelectric Rashba semiconductors (FERSCs) have recently attracted intensive attention due to their giant bulk Rashba parameter, αR, which results in a locking between the spin degrees of freedom and the switchable electric polarization. However, the integration of FERSCs into microelectronic devices has provoked questions concerning whether the Rashba effect can persist when the material thickness is reduced to several nanometers. Here we find that αR can keep a large value of 2.12 eV Å in the 5.0 nm thick GeTe film. The behavior of αR with thickness can be expressed by the scaling law and provides a 3D thickness limit of the bulk Rashba effect, dc = 2.1 ± 0.5 nm. Finally, we find that the thickness can modify the Berry curvature as well, which influences the polarization and consequently alters the αR. Our results give insight into understanding the factors influencing αR in FERSCs and pave a novel route for designing Rashba-type quantum materials.

In Silico Prediction and Validation of CB2 Allosteric Binding Sites to Aid the Design of Allosteric Modulators.

Although the 3D structures of active and inactive cannabinoid receptors type 2 (CB2) are available, neither the X-ray crystal nor the cryo-EM structure of CB2-orthosteric ligand-modulator has been resolved, prohibiting the drug discovery and development of CB2 allosteric modulators (AMs). In the present work, we mainly focused on investigating the potential allosteric binding site(s) of CB2. We applied different algorithms or tools to predict the potential allosteric binding sites of CB2 with the existing agonists. Seven potential allosteric sites can be observed for either CB2-CP55940 or CB2-WIN 55,212-2 complex, among which sites B, C, G and K are supported by the reported 3D structures of Class A GPCRs coupled with AMs. Applying our novel algorithm toolset-MCCS, we docked three known AMs of CB2 including Ec2la (C-2), trans-ß-caryophyllene (TBC) and cannabidiol (CBD) to each site for further comparisons and quantified the potential binding residues in each allosteric binding site. Sequentially, we selected the most promising binding pose of C-2 in five allosteric sites to conduct the molecular dynamics (MD) simulations. Based on the results of docking studies and MD simulations, we suggest that site H is the most promising allosteric binding site. We plan to conduct bio-assay validations in the future.

Inhibition of TLR4 signaling protects mice from sensory and motor dysfunction in an animal model of autoimmune peripheral neuropathy.

BACKGROUND: While the etiology remains elusive, macrophages and T cells in peripheral nerves are considered as effector cells mediating autoimmune peripheral neuropathy (APN), such as Guillain-Barre syndrome. By recognizing both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) signals, TLRs play a central role in the initiation of both innate and adaptive immune responses. In this study, we aimed to understand the involvement of TLR4 in the pathogenesis of APN and explore the potential of TLR4 as a drug target for therapeutic use. METHODS: APN was induced by a partial ligation on one of the sciatic nerves in B7.2 (L31) transgenic mice which possess a predisposed inflammatory background. APN pathology and neurological function were evaluated on the other non-injured sciatic nerve. RESULTS: TLR4 and its endogenous ligand HMGB1 were highly expressed in L31 mice, in circulating immune cells and in peripheral nerves. Enhanced TLR4 signaling was blocked with TAK 242, a selective TLR4 inhibitor, before and after disease onset. Intraperitoneal administration of TAK 242 not only inhibited monocyte, macrophage and CD8+ T cell activation, but also reduced the release of pro-inflammatory cytokines. TAK 242 protected mice from severe myelin and axonal loss, resulting in a remarkable improvement in mouse motor and sensory functions. TAK 242 was effective in alleviating the disease in both preventive and reversal paradigms. CONCLUSION: The study identified the critical contribution of TLR4-mediated macrophage activation in disease course and provided strong evidence to support TLR4 as a useful drug target for treating inflammatory autoimmune neuropathy.

Photosensitizer-free synthesis of ß-keto sulfones via visible-light-induced oxysulfonylation of alkenes with sulfonic acids.

A practical and environment-friendly methodology for the construction of ß-keto sulfones through visible-light induced direct oxysulfonylation of alkenes with sulfonic acids at ambient temperature under open-air conditions was developed. Most importantly, the reaction proceeded smoothly without the addition of any photocatalyst or strong oxidant, ultimately minimizing the production of chemical waste.

A rare case of thymic carcinoid presenting with gastrointestinal symptoms and pericardium effusion.

BACKGROUND: Thymic carcinoid is one of an extremely rare type of malignant neuroendocrine tumor with a poor prognosis. Invasion of thymic carcinoid to other organs could lead to devastating consequences. It has been reported that thymic carcinoid mainly invaded to the pleura, lungs, liver, pancreas and bone, while rarely to the cardiac, especially to the ventricle. CASE PRESENTATION: A 53-year-old man presented with gastrointestinal symptoms and persistent pericardial effusion. Multiple imaging tools, including chest computed tomography (CT), magnetic resonance imaging (MRI), 18F-Fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) showed a malignant neoplasm arising from the thymus invading into the biventricular myocardium, pericardium, and left superior pulmonary veins. The tumor was finally diagnosed as a thymic carcinoid through pathological examination. CONCLUSION: This is a rare case of thymic carcinoid invading the ventricular myocardium, which presented as subacute heart failure. The observations in this case would be useful for differential diagnosis of primary heart disease and invasion of heart due to thymic carcinoid.

miR-155-5p increases the sensitivity of liver cancer cells to adriamycin by regulating ATG5-mediated autophagy.

Liver cancer is the sixth most prevalent cancer worldwide and the third leading cause of cancer-related deaths. Adriamycin (ADR) resistance, which often leads to the progression of malignant tumors, is a major treatment obstacle for liver cancer. It has been confirmed that miR-155-5p could reverse drug resistance in human breast cancer. However, the biological function of miR-155-5p in ADR-resistant liver carcinoma (HepG2/ADR) cells remains unclear. miR-155-5p and ATG5 expression was determined by RT-qPCR and western blot. In addition, MTT, flow cytometry, immunofluorescence staining, and western blotting were performed to evaluate the proliferation, apoptosis, and autophagy of liver cancer cells. Finally, the effect of miR-155-5p on the expression of autophagy-related 5 (ATG5) was analyzed by luciferase activity assay, western blot, and RT-qPCR. Our results showed that miR-155-5p was downregulated in HepG2/ADR cells. Increasing the expression of miR-155-5p enhanced the sensitivity of liver carcinoma cells to ADR and promoted apoptosis through inhibition of autophagy in vitro. In addition, the binding site between miR-155-5p and ATG5 was identified, and miR-155-5p could directly regulate ATG5. Finally, ATG5 partially rescued the effect of miR-155-5p on autophagy and the apoptosis of HepG2/ADR cells. In conclusion, our findings showed that miR-155-5p could reverse ADR resistance in liver cancer by targeting ATG5, which may function as a potential target for liver cancer treatment.

N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis.

The conjugation of amino acids to the protein N termini is universally observed in eukaryotes and prokaryotes, yet its functions remain poorly understood. In eukaryotes, the amino acid l-arginine (l-Arg) is conjugated to N-terminal Asp (Nt-Asp), Glu, Gln, Asn, and Cys, directly or associated with posttranslational modifications. Following Nt-arginylation, the Nt-Arg is recognized by UBR boxes of N-recognins such as UBR1, UBR2, UBR4/p600, and UBR5/EDD, leading to substrate ubiquitination and proteasomal degradation via the N-end rule pathway. It has been a mystery, however, why studies for the past five decades identified only a handful of Nt-arginylated substrates in mammals, although five of 20 principal amino acids are eligible for arginylation. Here, we show that the Nt-Arg functions as a bimodal degron that directs substrates to either the ubiquitin (Ub)-proteasome system (UPS) or macroautophagy depending on physiological states. In normal conditions, the arginylated forms of proteolytic cleavage products, D101-CDC6 and D1156-BRCA1, are targeted to UBR box-containing N-recognins and degraded by the proteasome. However, when proteostasis by the UPS is perturbed, their Nt-Arg redirects these otherwise cellular wastes to macroautophagy through its binding to the ZZ domain of the autophagic adaptor p62/STQSM/Sequestosome-1. Upon binding to the Nt-Arg, p62 acts as an autophagic N-recognin that undergoes self-polymerization, facilitating cargo collection and lysosomal degradation of p62-cargo complexes. A chemical mimic of Nt-Arg redirects Ub-conjugated substrates from the UPS to macroautophagy and promotes their lysosomal degradation. Our results suggest that the Nt-Arg proteome of arginylated proteins contributes to reprogramming global proteolytic flux under stresses.