The TRAF3-DYRK1A-RAD54L2 complex maintains ACE2 expression to promote SARS-CoV-2 infection.

Angiotensin converting enzyme 2 (ACE2), the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is differentially expressed in a wide variety of tissues and cell types. The expression of ACE2 is under tight regulation, but the mechanisms regulating ACE2 expression have not yet been well defined. Through a genome-wide CRISPR knockout screen, we discovered that host factors TRAF3, DYRK1A, and RAD54L2 (TDR) form a complex to regulate the expression of ACE2. Knockout of TRAF3, DYRK1A, or RAD54L2 reduces the mRNA levels of ACE2 and inhibits the cellular entry of SARS-CoV-2. On the other hand, SARS-CoV-2 continuously evolves by genetic mutations for the adaption to the host. We have identified mutations in spike (S) (P1079T) and nucleocapsid (N) (S194L) that enhance the replication of SARS-CoV-2 in cells that express ACE2 at a low level. Our results have revealed the mechanisms for the transcriptional regulation of ACE2 and the adaption of SARS-CoV-2. IMPORTANCE: The expression of ACE2 is essential for the entry of SARS-CoV-2 into host cells. We identify a new complex-the TDR complex-that acts to maintain the abundance of ACE2 in host cells. The identification and characterization of the TDR complex provide new targets for the development of therapeutics against SARS-CoV-2 infection. By analysis of SARS-CoV-2 virus replicating in cells expressing low levels of ACE2, we identified mutations in spike (P1079T) and nucleocapsid (S194L) that overcome the restriction of limited ACE2. Functional analysis of these key amino acids in S and N extends our knowledge of the impact of SARS-CoV-2 variants on virus infection and transmission.

Synergetic Dual-Additive Electrolyte Enables Highly Stable Performance in Sodium Metal Batteries.

Sodium (Na)-metal batteries (SMBs) are considered one of the most promising candidates for the large-scale energy storage market owing to their high theoretical capacity (1,166 mAh g-1) and the abundance of Na raw material. However, the limited stability of electrolytes still hindered the application of SMBs. Herein, sulfolane (Sul) and vinylene carbonate (VC) are identified as effective dual additives that can largely stabilize propylene carbonate (PC)-based electrolytes, prevent dendrite growth, and extend the cycle life of SMBs. The cycling stability of the Na/NaNi0.68Mn0.22Co0.1O2 (NaNMC) cell with this dual-additive electrolyte is remarkably enhanced, with a capacity retention of 94% and a Coulombic efficiency (CE) of 99.9% over 600 cycles at a 5 C (750 mA g-1) rate. The superior cycling performance of the cells can be attributed to the homogenous, dense, and thin hybrid solid electrolyte interphase consisting of F- and S-containing species on the surface of both the Na metal anode and the NaNMC cathode by adding dual additives. Such unique interphases can effectively facilitate Na-ion transport kinetics and avoid electrolyte depletion during repeated cycling at a very high rate of 5 C. This electrolyte design is believed to result in further improvements in the performance of SMBs.

Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma.

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.

Utilization of Ultrafine Gas Bubbles to Investigate the Jones-Ray Effect of Diluted Salt Solutions.

The cause of the Jones-Ray effect has been controversially debated for years. Ultrafine gas bubbles were employed to lessen the surface excess of the surface-active impurities adsorbing to the air/water interface of the salt solutions, which would lead to a direct shift in surface tension observable by the Wilhelmy plate method. It was concluded in this study that once the surface excess of the inevitable impurities in the salts is lessened by the introduction of ultrafine gas bubbles, which possess great air/water interfacial area, the Jones-Ray effect becomes nonobservable. Therefore, our finding hypothesized that the Jones-Ray effect might not originate from salts.

High titer methyl ketone production with tailored Pseudomonas taiwanensis VLB120.

Methyl ketones present a group of highly reduced platform chemicals industrially produced from petroleum-derived hydrocarbons. They find applications in the fragrance, flavor, pharmacological, and agrochemical industries, and are further discussed as biodiesel blends. In recent years, intense research has been carried out to achieve sustainable production of these molecules by re-arranging the fatty acid metabolism of various microbes. One challenge in the development of a highly productive microbe is the high demand for reducing power. Here, we engineered Pseudomonas taiwanensis VLB120 for methyl ketone production as this microbe has been shown to sustain exceptionally high NAD(P)H regeneration rates. The implementation of published strategies resulted in 2.1 g Laq-1 methyl ketones in fed-batch fermentation. We further increased the production by eliminating competing reactions suggested by metabolic analyses. These efforts resulted in the production of 9.8 g Laq-1 methyl ketones (corresponding to 69.3 g Lorg-1 in the in situ extraction phase) at 53% of the maximum theoretical yield. This represents a 4-fold improvement in product titer compared to the initial production strain and the highest titer of recombinantly produced methyl ketones reported to date. Accordingly, this study underlines the high potential of P. taiwanensis VLB120 to produce methyl ketones and emphasizes model-driven metabolic engineering to rationalize and accelerate strain optimization efforts.

Epstein-Barr virus latency type and spontaneous reactivation predict lytic induction levels.

The human Epstein-Barr virus (EBV) evades the immune system by entering a transcriptionally latent phase in B cells. EBV in tumor cells expresses distinct patterns of genes referred to as latency types. Viruses in tumor cells also display varying levels of lytic transcription resulting from spontaneous reactivation out of latency. We measured this dynamic range of lytic transcription with RNA deep sequencing and observed no correlation with EBV latency types among genetically different viruses, but type I cell lines reveal more spontaneous reactivation than isogenic type III cultures. We further determined that latency type and spontaneous reactivation levels predict the relative amount of induced reactivation generated by cytotoxic chemotherapy drugs. Our work has potential implications for personalizing medicine against EBV-transformed malignancies. Identifying latency type or measuring spontaneous reactivation may provide predictive power in treatment contexts where viral production should be either avoided or coerced.

PTEN Mediates the Silencing of Unintegrated HIV-1 DNA.

The integration of viral DNA into a host genome is an important step in HIV-1 replication. However, due to the high failure rate of integration, the majority of viral DNA exists in an unintegrated state during HIV-1 infection. In contrast to the robust expression from integrated viral DNA, unintegrated HIV-1 DNA is very poorly transcribed in infected cells, but the molecular machinery responsible for the silencing of unintegrated HIV-1 DNA remains poorly characterized. In this study, we sought to characterize new host factors for the inhibition of expression from unintegrated HIV-1 DNA. A genome-wide CRISPR-Cas9 knockout screening revealed the essential role of phosphatase and tensin homolog (PTEN) in the silencing of unintegrated HIV-1 DNA. PTEN's phosphatase activity negatively regulates the PI3K-Akt pathway to inhibit the transcription from unintegrated HIV-1 DNA. The knockout (KO) of PTEN or inhibition of PTEN's phosphatase activity by point mutagenesis activates Akt by phosphorylation and enhances the transcription from unintegrated HIV-1 DNA. Inhibition of the PI3K-Akt pathway by Akt inhibitor in PTEN-KO cells restores the silencing of unintegrated HIV-1 DNA. Transcriptional factors (NF-κB, Sp1, and AP-1) are important for the activation of unintegrated HIV-1 DNA in PTEN-KO cells. Finally, the knockout of PTEN increases the levels of active epigenetic marks (H3ac and H3K4me3) and the recruitment of PolII on unintegrated HIV-1 DNA chromatin. Our experiments reveal that PTEN targets transcription factors (NF-κB, Sp1, and AP-1) by negatively regulating the PI3K-Akt pathway to promote the silencing of unintegrated HIV-1 DNA.

Unlocking the potentials of Ustilago trichophora for up-cycling polyurethane-derived monomer 1,4-butanediol.

Plastic usage by microbes as a carbon source is a promising strategy to increase the recycling quota. 1,4-butanediol (BDO) is a common monomer derived from polyesters and polyurethanes. In this study, Ustilago trichophora was found to be an efficient cell-factory to valorize BDO. To investigate product formation by U. trichophora, we refined the traditional ion exclusion liquid chromatography method by examining eluent, eluent concentrations, oven temperatures, and organic modifiers to make the chromatography compatible with mass spectrometry. An LC-UV/RI-MS2 method is presented here to identify and quantify extracellular metabolites in the cell cultures. With this method, we successfully identified that U. trichophora secreted malic acid, succinic acid, erythritol, and mannitol into the culture medium. Adaptive laboratory evolution followed by medium optimization significantly improved U. trichophora growth on BDO and especially malic acid production. Overall, the carbon yield on the BDO substrate was approximately 33% malic acid. This study marks the first report of a Ustilaginaceae fungus capable of converting BDO into versatile chemical building blocks. Since U. trichophora is not genetically engineered, it is a promising microbial host to produce malic acid from BDO, thereby contributing to the development of the envisaged sustainable bioeconomy.

Revealing the Anion-Solvent Interaction for Ultralow Temperature Lithium Metal Batteries.

Anion solvation in electrolytes can largely change the electrochemical performance of the electrolytes, yet has been rarely investigated. Herein, three anions of bis(trifluoromethanesulfonyl)imide (TFSI), bis(fluorosulfonyl)imide (FSI), and derived asymmetric (fluorosulfonyl)(trifluoro-methanesulfonyl)imide (FTFSI) are systematically examined in a weakly Li+ cation solvating solvent of bis(3-fluoropropyl)ether (BFPE). In-situ liquid secondary ion mass spectrometry demonstrates that FTFSI- and FSI- anions are associated with BFPE solvent, while weak TFSI- /BFPE cluster signals are detected. Molecular modeling further reveals that the anion-solvent interaction is accompanied by the formation of H-bonding-like interactions. Anion solvation enhances the Li+ cation transfer number and reduces the organic component in solid electrolyte interphase, which enhances the Li plating/stripping Coulombic efficiency at a low temperature of -30 °C from 42.4% in TFSI-based electrolytes to 98.7% in 1.5 m LiFTFSI and 97.9% in LiFSI-BFPE electrolytes. The anion-solvent interactions, especially asymmetric anion solvation also accelerate the Li+ desolvation kinetics. The 1.5 m LiFTFSI-BFPE electrolyte with strong anion-solvent interaction enables LiNi0.8 Mn0.1 Co0.1 O2 (NMC811)||Li (20 µm) full cell with stable cyclability even under -40 °C, retaining over 92% of initial capacity (115 mAh g-1 , after 100 cycles). The anion-solvent interactions insights allow to rational design the electrolyte for lithium metal batteries and beyond to achieve high performance.

Lightweight electrolyte design for Li/sulfurized polyacrylonitrile (SPAN) batteries.

Sulfurized polyacrylonitrile (SPAN) has recently emerged as a promising cathode for high-energy Li metal batteries owing to its high capacity, extended cycle life, and liberty from costly transition metals. As the high capacities of both Li metal and SPAN lead to relatively small electrode weights, the weight and specific energy density of Li/SPAN batteries are particularly sensitive to electrolyte weight, highlighting the importance of minimizing electrolyte density. In addition, the large volume changes of Li metal anode and SPAN cathode require inorganic-rich interphases that can guarantee intactness and protectivity throughout long cycles. This work addresses these crucial aspects with an electrolyte design in which lightweight dibutyl ether (DBE) is used as diluent for concentrated LiFSI-triethyl phosphate (TEP) solution. The designed electrolyte (d = 1.04 g mL-1) is 40-50% lighter than conventional localized high-concentration electrolytes (LHCEs), leading to 12-20% extra energy density at the cell level. Besides, the use of DBE introduces substantial solvent-diluent affinity, resulting in a unique solvation structure with strengthened capability to form favorable anion-derived inorganic-rich interphases, minimize electrolyte consumption, and improve cell cyclability. Our electrolyte also exhibits lower volatility than carbonate electrolytes and offers enhanced protection to both Li metal anode and SPAN cathode under thermal abuse. This article is protected by copyright. All rights reserved.

Alignment of multimodal sensory input in the superior colliculus through a gradient-matching mechanism.

The superior colliculus (SC) is a midbrain structure that integrates visual, somatosensory, and auditory inputs to direct head and eye movements. Each of these modalities is topographically mapped and aligned with the others to ensure precise behavioral responses to multimodal stimuli. While it is clear that neural activity is instructive for topographic alignment of inputs from the visual cortex (V1) and auditory system with retinal axons in the SC, there is also evidence that activity-independent mechanisms are used to establish topographic alignment between modalities. Here, we show that the topography of the projection from primary somatosensory cortex (S1) to the SC is established during the first postnatal week. Unlike V1-SC projections, the S1-SC projection does not bifurcate when confronted with a duplicated retinocollicular map, showing that retinal input in the SC does not influence the topography of the S1-SC projection. However, S1-SC topography is disrupted in mice lacking ephrin-As, which we find are expressed in graded patterns along with their binding partners, the EphA4 and EphA7, in both S1 and the somatosensory recipient layer of the SC. Together, these data support a model in which somatosensory inputs into the SC map topographically and establish alignment with visual inputs in the SC using a gradient-matching mechanism.

Improvement of the Impacted Level of Lower Third Molars After Orthodontic Treatment.

OBJECTIVES: The early or delayed surgical removal of an asymptomatic lower third molar (M3) in orthodontic patients remains controversial. This study aimed to determine the changes in the impacted level of M3 such as angulation, vertical position, and eruption space, after orthodontic treatment in 3 groups, namely non-extraction (NE), first premolar (P1) extraction, and second premolar (P2) extraction. METHODS: Relevant angles and distances related to 334 M3s from 180 orthodontic patients were assessed pre- and posttreatment. Angle between lower second molar (M2) and M3 (M3-M2) was used for evaluating M3 angulation. For M3 vertical position, distances from occlusal plane to the highest cuspid (Cus-OP) and fissure (Fis-OP) of M3 were used. Distances from the distal surface of M2 to anterior border (J-DM2) and centre (Xi-DM2) of the ramus were used for assessing M3 eruption space. Pre- and posttreatment values of the angle and distance in each group were compared using a paired-sample t test. Measurements of the 3 groups were compared using analysis of variance. Hence, multiple linear regression (MLR) analysis was used to determine significant factors that impacted changes in M3s' related measurements. Independent factors used for MLR analysis included sex, treatment starting age, pretreatment respective angle/distance, and premolar extraction (NE/P1/P2). RESULTS: M3 angulation, vertical position, and eruption space at posttreatment were significantly different from those at pretreatment in all 3 groups. MLR analysis showed that P2 extraction significantly improved M3 vertical position (P < .05) and eruption space (P < .001). P1 extraction significantly decreased Cus-OP (P = .014) and eruption space (P < .001). Treatment starting age was significant factor that affected Cus-OP (P = .001) and M3 eruption space (P < .001). CONCLUSIONS: After orthodontic treatment, M3 angulation, vertical position, and eruption space changed in favour of the impacted level. These changes in the 3 groups were clearer in order: NE, P1, and P2, respectively.

Renewable carbon sources to biochemicals and -fuels: contributions of the smut fungi Ustilaginaceae.

The global demand for food, fuels, and chemicals increases annually. Using renewable C-sources (i.e. biomass, CO2, and organic waste) is a prerequisite for a future free of fossil carbon. The smut fungi Ustilaginaceae naturally produce a versatile spectrum of valuable products, such as organic acids, polyols, and glycolipids, applicable in the food, energy, chemistry, and pharmaceutical sector. Combined with the use of alternative (co-)substrates (e.g. acetate, butanediol, formate, and glycerol), these microorganisms offer excellent potential for industrial biotechnology, thereby overcoming central challenges humankind faces, including CO2 release and land use. Here, we provide insight into fundamental production capacities, present genetic modifications that improve the biotechnical application, and review recent high-performance engineering of Ustilaginaceae toward relevant platform chemicals.

High-quality physiology of Alcanivorax borkumensis SK2 producing glycolipids enables efficient stirred-tank bioreactor cultivation.

Glycine-glucolipid, a glycolipid, is natively synthesized by the marine bacterium Alcanivorax borkumensis SK2. A. borkumensis is a Gram-negative, non-motile, aerobic, halophilic, rod-shaped γ-proteobacterium, classified as an obligate hydrocarbonoclastic bacterium. Naturally, this bacterium exists in low cell numbers in unpolluted marine environments, but during oil spills, the cell number significantly increases and can account for up to 90% of the microbial community responsible for oil degradation. This growth surge is attributed to two remarkable abilities: hydrocarbon degradation and membrane-associated biosurfactant production. This study aimed to characterize and enhance the growth and biosurfactant production of A. borkumensis, which initially exhibited poor growth in the previously published ONR7a, a defined salt medium. Various online analytic tools for monitoring growth were employed to optimize the published medium, leading to improved growth rates and elongated growth on pyruvate as a carbon source. The modified medium was supplemented with different carbon sources to stimulate glycine-glucolipid production. Pyruvate, acetate, and various hydrophobic carbon sources were utilized for glycolipid production. Growth was monitored via online determined oxygen transfer rate in shake flasks, while a recently published hyphenated HPLC-MS method was used for glycine-glucolipid analytics. To transfer into 3 L stirred-tank bioreactor, aerated batch fermentations were conducted using n-tetradecane and acetate as carbon sources. The challenge of foam formation was overcome using bubble-free membrane aeration with acetate as the carbon source. In conclusion, the growth kinetics of A. borkumensis and glycine-glucolipid production were significantly improved, while reaching product titers relevant for applications remains a challenge.

HIV-1 exploits the Fanconi anemia pathway for viral DNA integration.

The integration of HIV-1 DNA into the host genome results in single-strand gaps and 2-nt overhangs at the ends of viral DNA, which must be repaired by cellular enzymes. The cellular factors responsible for the DNA damage repair in HIV-1 DNA integration have not yet been well defined. We report here that HIV-1 infection potently activates the Fanconi anemia (FA) DNA repair pathway, and the FA effector proteins FANCI-D2 bind to the C-terminal domain of HIV-1 integrase. Knockout of FANCI blocks productive viral DNA integration and inhibits the replication of HIV-1. Finally, we show that the knockout of DNA polymerases or flap nuclease downstream of FANCI-D2 reduces the levels of integrated HIV-1 DNA, suggesting these enzymes may be responsible for the repair of DNA damages induced by viral DNA integration. These experiments reveal that HIV-1 exploits the FA pathway for the stable integration of viral DNA into host genome.

Genomic and transcriptomic profiling reveals distinct molecular subsets associated with outcomes in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1-C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.

Special Issue "Metabolic Engineering and Synthetic Biology Volume 2".

In times of ever-increasing demand for chemicals and the subsequent increase in CO2 in the atmosphere, we have to intensify our efforts to establish a circular (bio) economy [...].

Ustilaginaceae Biocatalyst for Co-Metabolism of CO2-Derived Substrates toward Carbon-Neutral Itaconate Production.

The family Ustilaginaceae (belonging to the smut fungi) are known for their plant pathogenicity. Despite the fact that these plant diseases cause agricultural yield reduction, smut fungi attracted special attention in the field of industrial biotechnology. Ustilaginaceae show a versatile product spectrum such as organic acids (e.g., itaconate, malate, succinate), polyols (e.g., erythritol, mannitol), and extracellular glycolipids, which are considered value-added chemicals with potential applications in the pharmaceutical, food, and chemical industries. This study focused on itaconate as a platform chemical for the production of resins, plastics, adhesives, and biofuels. During this work, 72 different Ustilaginaceae strains from 36 species were investigated for their ability to (co-) consume the CO2-derived substrates acetate and formate, potentially contributing toward a carbon-neutral itaconate production. The fungal growth and product spectrum with special interest in itaconate was characterized. Ustilago maydis MB215 and Ustilago rabenhorstiana NBRC 8995 were identified as promising candidates for acetate metabolization whereas Ustilago cynodontis NBRC 7530 was identified as a potential production host using formate as a co-substrate enhancing the itaconate production. Selected strains with the best itaconate production were characterized in more detail in controlled-batch bioreactor experiments confirming the co-substrate utilization. Thus, a proof-of-principle study was performed resulting in the identification and characterization of three promising Ustilaginaceae biocatalyst candidates for carbon-neutral itaconate production contributing to the biotechnological relevance of Ustilaginaceae.

Utilizing polymer-conjugate albumin-based ultrafine gas bubbles in combination with ultra-high frequency radiations in drug transportation and delivery.

The application of ultrafine bubbles as drug carriers in drug delivery is still in its developmental stage; it is important to obtain a thorough understanding of the factors affecting the formation and stability of drug carrier matrices. In this study, the polyethylene glycol (PEG)-conjugated human serum albumin (HSA)-based ultrafine bubble simulating the physiological electrolyte concentration in human blood (154 mM) for quercetin delivery was investigated. Optical absorbance measurements, surface tension measurements, and fluorescence laser imaging were also employed to assess the plausibility of polymer-conjugated albumin-stabilized ultrafine bubbles in drug loading and drug release. The incorporation of PEG/HSA into the system illustrated a significant enhancement in the matrix's stability as confirmed by surface tension measurements and drug-loading efficiency achieving approximately 90%. In addition, in vitro drug release was performed by the application of high-frequency ultrasound, indicating more than 40% of the loaded quercetin was astonishingly liberated within 5 minutes of exposure.

A putative long noncoding RNA-encoded micropeptide maintains cellular homeostasis in pancreatic ß cells.

Micropeptides (microproteins) encoded by transcripts previously annotated as long noncoding RNAs (lncRNAs) are emerging as important mediators of fundamental biological processes in health and disease. Here, we applied two computational tools to identify putative micropeptides encoded by lncRNAs that are expressed in the human pancreas. We experimentally verified one such micropeptide encoded by a ß cell- and neural cell-enriched lncRNA TCL1 Upstream Neural Differentiation-Associated RNA (TUNAR, also known as TUNA, HI-LNC78, or LINC00617). We named this highly conserved 48-amino-acid micropeptide beta cell- and neural cell-regulin (BNLN). BNLN contains a single-pass transmembrane domain and localizes at the endoplasmic reticulum (ER) in pancreatic ß cells. Overexpression of BNLN lowered ER calcium levels, maintained ER homeostasis, and elevated glucose-stimulated insulin secretion in pancreatic ß cells. We further assessed the BNLN expression in islets from mice fed a high-fat diet and a regular diet and found that BNLN is suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN enhanced insulin secretion in islets from lean and obese mice as well as from humans. Taken together, our study provides the first evidence that lncRNA-encoded micropeptides play a critical role in pancreatic ß cell functions and provides a foundation for future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes.