Pulmonary manifestations of VEXAS syndrome with acute interstitial pneumonia and diffuse alveolar hemorrhage: a case report and literature review.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an emerging adult-onset systemic autoinflammatory disorder affecting multiple organ systems. While lung involvement is common in this syndrome, literature regarding specific patterns is sparse. In this report, we present a case description of a patient with VEXAS syndrome who presented at the emergency department on two separate occasions with acute interstitial pneumonia (AIP) and diffuse alveolar hemorrhage (DAH). A literature review with a comparison of our observed findings to the general findings of VEXAS syndrome, AIP, and DAH is provided. This report underscores the rarity of specific pulmonary manifestations associated with VEXAS syndrome, contributing valuable insight to the limited literature available on this topic.

Case report: VEXAS syndrome: an atypical indolent presentation as sacroiliitis with molecular response to azacitidine.

VEXAS syndrome is a recently described autoinflammatory syndrome caused by the somatic acquisition of UBA1 mutations in myeloid precursors and is frequently associated with hematologic malignancies, chiefly myelodysplastic syndromes. Disease presentation can mimic several rheumatologic disorders, delaying the diagnosis. We describe a case of atypical presentation resembling late-onset axial spondylarthritis, later progressing to a systemic inflammatory syndrome with chondritis, cutaneous vasculitis, and transfusion-dependent anemia, requiring high doses of steroids. Ruxolitinib was used as the first steroid-sparing strategy without response. However, azacitidine showed activity in controlling both inflammation and the mutant clone. This case raises the question of whether azacitidine's anti-inflammatory effects are dependent on or independent of clonal control. We discuss the potential relevance of molecular remission in VEXAS syndrome and highlight the importance of a multidisciplinary team for the care of such complex patients.

The heterogeneity of lung involvement in vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome: a case of hypersensitivity pneumonitis-like pattern.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently characterized disease associated with somatic mutations in the UBA1 gene, which cause dysregulation of ubiquitin-mediated processes. This case describes a 71-year-old male patient with VEXAS syndrome who presented with refractory lung inflammation with a pattern similar to computed tomography hypersensitivity pneumonitis, a novel finding in VEXAS syndrome. The presented clinical case highlights the protean involvement of the lung in VEXAS syndrome and emphasizes the importance of considering interstitial lung disease in the differential diagnosis.

Central nervous system vasculitis in VEXAS syndrome: A rare involvemen.

INTRODUCTION: VEXAS (Vacuoles, E1 Enzyme, X-linked, autoinflammatory, Somatic) syndrome is a recently described severe adult-onset autoinflammatory disorder mediated by X-linked gene UBA1 somatic mutations, responsible of recurrent fever, skin involvement, chondritis, macrocytic anemia and inflammatory syndrome. Neurological manifestations are rarely described, and predominantly involve peripheral nervous system (PNS) impairment. RESULTS: We report the first central nervous system (CNS) vasculitis in VEXAS syndrome, characterized by headache, cognitive dysfunction and focal signs (cerebellar ataxia). Magnetic resonance imaging (MRI) revealed multifocal white-matter lesions corresponding to recent ischemic strokes, combined with cortical hemorrhagic lesions and gadolinium enhancement of the distal wall vessels. Treatment with methylprednisone, ruxolitinib and tocilizumab led to clinical improvement and a decrease of the inflammatory syndrome. The patient died few months after due to infectious complications. CONCLUSION: CNS vasculitis, occurring as a manifestation of the systemic auto-inflammatory state of VEXAS syndrome, might be a rare but severe complication. We suggest that it be added to the list of inflammatory vasculopathies. More prospective studies are needed to optimize the treatment.

Juvenile dermatomyositis with Anti-SAE antibodies in a Moroccan child associated with pseudo-angioedema: a case report.

BACKGROUND: Juvenile Dermatomyositis (JDM) is the leading cause of non-infectious inflammatory myopathy in children. It is a heterogeneous group of autoimmune diseases characterized by a variable combination of muscular, dermatological, and visceral involvement. Myositis-specific autoantibodies help define homogeneous subgroups with common clinical characteristics and prognoses. Anti-SAE (small ubiquitin-like modifier 1 (SUMO-1) activating enzyme) antibodies are among the most recently discovered specific autoantibodies. The presence of these antibodies is very rare, making it challenging to define clinical features and prognosis in the juvenile form. We report the first case of an African patient with juvenile dermatomyositis and positive anti-SAE antibodies. CASE REPORT: A 5-year-3-month-old Moroccan boy presented to the pediatric emergency department with dysphagia that had been evolving for two days, preceded two months earlier by facial erythema associated with fatigue, lower limb pain, difficulty walking, and progressive inflammatory polyarthralgia. On admission, the child had a heliotrope rash with predominant pseudo-angioedema on the lips, periungual telangiectasia, and Gottron's papules over the bilateral interphalangeal and metatarsophalangeal joints. The patient had a more pronounced proximal muscle weakness in the lower limbs. He had no urticaria, fever, arthritis, calcinosis, cutaneous ulcers, or lipodystrophy. The Joint examination was normal, as was the pleuropulmonary examination. The electroneuromyography showed myogenic changes in all four limbs. Laboratory findings showed elevated levels of creatine phosphokinase and lactate dehydrogenase and a mild inflammatory syndrome. The electrocardiogram was normal. The anti-SAE antibodies were positive. The boy was diagnosed with juvenile dermatomyositis. He received methylprednisolone bolus therapy followed by oral prednisone. The latter was gradually tapered in combination with weekly intramuscular methotrexate. As a result, dysphagia disappeared within 48 h. After two weeks, there was an improvement in the muscular score and a significant regression of facial pseudo-angioedema. CONCLUSION: We report the first African patient with anti-SAE autoantibody-positive JDM. He had a typical dermatological manifestation of JDM associated with pseudo-angioedema predominant on the lips; a rarely reported sign in DM and JDM patients. The patient responded well to corticosteroid therapy and methotrexate.

Discovery of a DCAF11-dependent cyanoacrylamide-containing covalent degrader of BET-proteins.

Targeted protein degradation is mediated by small molecules that induce or stabilize protein-protein interactions between targets and the ubiquitin-proteasome machinery. Currently, there remains a need to expand the repertoire of viable E3 ligases available for hijacking. Notably, covalent chemistry has been employed to engage a handful of E3 ligases, including DCAF11. Here, we disclose a covalent PROTAC that enables DCAF11-dependent degradation, featuring a cyanoacrylamide warhead. Our findings underscore DCAF11 as an interesting candidate with a capacity to accommodate diverse electrophilic chemistries compatible with targeted protein degradation.

The NEDD8 activating enzyme inhibitor MLN4924 mitigates doxorubicin-induced cardiotoxicity in mice.

Doxorubicin (DOX) is a widely utilized chemotherapeutic agent in clinical oncology for treating various cancers. However, its clinical use is constrained by its significant side effects. Among these, the development of cardiomyopathy, characterized by cardiac remodeling and eventual heart failure, stands as a major concern following DOX chemotherapy. In our current investigation, we have showcased the efficacy of MLN4924 in mitigating doxorubicin-induced cardiotoxicity through direct inhibition of the NEDD8-activating enzyme, NAE. MLN4924 demonstrated the ability to stabilize mitochondrial function post-doxorubicin treatment, diminish cardiomyocyte apoptosis, alleviate oxidative stress-induced damage in the myocardium, enhance cardiac contractile function, mitigate cardiac fibrosis, and impede cardiac remodeling associated with heart failure. At the mechanistic level, MLN4924 intervened in the neddylation process by inhibiting the NEDD8 activating enzyme, NAE, within the murine cardiac tissue subsequent to doxorubicin treatment. This intervention resulted in the suppression of NEDD8 protein expression, reduction in neddylation activity, and consequential manifestation of cardioprotective effects. Collectively, our findings posit MLN4924 as a potential therapeutic avenue for mitigating doxorubicin-induced cardiotoxicity by attenuating heightened neddylation activity through NAE inhibition, thereby offering a viable and promising treatment modality for afflicted patients.

UBA2 as a Prognostic Biomarker and Potential Therapeutic Target in Glioma.

BACKGROUND: Gliomas are characterized by aggressive behavior, leading to severe disability and high mortality. Ubiquitin-like modifier activating enzyme 2 (UBA2) is a subunit of the E1-activating enzyme involved in the SUMOylation (SUMO, small ubiquitin-related modifier) of numerous proteins. Although the abnormality of UBA2 is linked to the progression of various tumor types, the role of UBA2 in glioma is still unknown. METHODS: A bioinformatic analysis using several public databases was conducted to examine the expression level, clinicopathological correlations, and prognostic significance of UBA2 in glioma. The correlation between UBA2 expression and drug sensitivity in cancers was also explored. Multiple cellular experiments were conducted to validate the role of UBA2 in glioma. RESULTS: Analysis of multiple databases and cellular experiments revealed that UBA2 was overexpressed in glioma tissues and cell lines, respectively. UBA2 expression in gliomas correlated with World Health Organization (WHO) grade, IDH gene status, 1p19q deletion, histological type, and immune cell infiltration in glioma. UBA2 expression in carcinomas also correlated with drug sensitivity. Kaplan-Meier analysis revealed that high expression of UBA2 predicted poorer survival in glioma patients. A nomogram model containing UBA2 expression was constructed for clinical practice. Knockdown of UBA2 was observed to suppress glioma cell progression and sensitize glioma cells to irradiation in vitro. CONCLUSION: Overall, this research showed that UBA2 might be involved not only in the development of glioma but also in the regulation of immunity, drug sensitivity, and radiosensitivity. Therefore, UBA2 may be a potential target for therapy and a candidate biomarker for glioma diagnosis and prognosis.

[Clinical and genetic features of MDS associated with VEXAS syndrome].

VEXAS syndrome is a new disease entity characterized by the presence of cytoplasmic vacuoles in blood cells, X-linked autoinflammatory symptoms, and somatic variants in UBA1, which encodes an E1 ubiquitin-activating enzyme. Around 30-50% of VEXAS syndrome patients have concurrent MDS. We and others have recently analyzed clinical and genetic features of MDS associated with VEXAS syndrome and found that most of these cases are categorized in the low-risk subgroup with low bone marrow blast percentages. MDS associated with VEXAS syndrome tended to involve a smaller number of genes and lower-risk genetic alterations than classical MDS. In addition, anemia in MDS associated with VEXAS syndrome with active inflammation before treatment tended to respond well to steroids. In this review, we will present our recent findings together with others, focusing on the new disease entity and pathophysiology of VEXAS syndrome and clinical/genetic features of associated MDS.

Insights on E1-like enzyme ATG7: functional regulation and relationships with aging-related diseases.

Autophagy is a dynamic self-renovation biological process that maintains cell homeostasis and is responsible for the quality control of proteins, organelles, and energy metabolism. The E1-like ubiquitin-activating enzyme autophagy-related gene 7 (ATG7) is a critical factor that initiates classic autophagy reactions by promoting the formation and extension of autophagosome membranes. Recent studies have identified the key functions of ATG7 in regulating the cell cycle, apoptosis, and metabolism associated with the occurrence and development of multiple diseases. This review summarizes how ATG7 is precisely programmed by genetic, transcriptional, and epigenetic modifications in cells and the relationship between ATG7 and aging-related diseases.

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK-243 in Adrenocortical Carcinoma Cell Lines, Patient-derived Organoids, and Murine Xenografts.

Current treatment options for metastatic adrenocortical carcinoma (ACC) have limited efficacy, despite the common use of mitotane and cytotoxic agents. This study aimed to identify novel therapeutic options for ACC. An extensive drug screen was conducted to identify compounds with potential activity against ACC cell lines. We further investigated the mechanism of action of the identified compound, TAK-243, its synergistic effects with current ACC therapeutics, and its efficacy in ACC models including patient-derived organoids and mouse xenografts. TAK-243, a clinical ubiquitin-activating enzyme (UAE) inhibitor, showed potent activity in ACC cell lines. TAK-243 inhibited protein ubiquitination in ACC cells, leading to the accumulation of free ubiquitin, activation of the unfolded protein response, and induction of apoptosis. TAK-243 was found to be effluxed out of cells by MDR1, a drug efflux pump, and did not require Schlafen 11 (SLFN11) expression for its activity. Combination of TAK-243 with current ACC therapies (e.g., mitotane, etoposide, cisplatin) produced synergistic or additive effects. In addition, TAK-243 was highly synergistic with BCL2 inhibitors (Navitoclax and Venetoclax) in preclinical ACC models including patient-derived organoids. The tumor suppressive effects of TAK-243 and its synergistic effects with Venetoclax were further confirmed in a mouse xenograft model. These findings provide preclinical evidence to support the initiation of a clinical trial of TAK-243 in patients with advanced-stage ACC. TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors. SIGNIFICANCE: ACC is a rare endocrine cancer with poor prognosis and limited therapeutic options. We report that TAK-243 is active alone and in combination with currently used therapies and with BCL2 and mTOR inhibitors in ACC preclinical models. Our results suggest implementation of TAK-243 in clinical trials for patients with advanced and metastatic ACC.

UBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells.

Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin-proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca2+ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells.

How I diagnose and manage VEXAS syndrome.

OBJECTIVES: To discuss VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, including the clinical and pathologic features, diagnostic challenges, and treatment options. METHODS: A case-based approach and pertinent literature review were used to highlight the features of VEXAS syndrome, describe how to make the diagnosis, and discuss available therapies. RESULTS: VEXAS syndrome is an adult-onset, progressive systemic inflammatory disorder with overlapping rheumatologic and hematologic manifestations, including an increased risk of myelodysplastic neoplasms and plasma cell neoplasms. The disorder is associated with a somatic mutation of the X-linked UBA1 gene involved in ubiquitylation, typically involving p.Met41; however, rare variations have been identified outside this region. Patients often present with complex histories and see physicians from multiple specialties before receiving the diagnosis, which is often delayed. Symptoms are related to inflammation as well as cytopenias, particularly macrocytic anemia. Characteristic cytoplasmic vacuoles are present in myeloid (granulocytic, monocytic) and erythroid precursors in the vast majority of cases. CONCLUSIONS: Either clinicians or pathologists may suspect a diagnosis of VEXAS syndrome depending on the clinical presentation and bone marrow findings. More studies are needed to determine the best therapeutic options, which are currently limited.

Ocular and orbital manifestations in VEXAS syndrome.

BACKGROUND: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a hematoinflammatory disease that typically affects adults. It results from a somatic mutation of the E1 ubiquitin conjugating enzyme encoded by the UBA1 gene. VEXAS is frequently accompanied by myelodysplastic syndrome (MDS). The purpose of this study is to describe the ocular and orbital manifestations of VEXAS patients in a case series in our medical centre. METHODS: A retrospective chart review was performed for all patients who were diagnosed with VEXAS syndrome in a tertiary medical centre over two years. RESULTS: Eight patients were identified with VEXAS. In six patients, the diagnosis was confirmed by genomic sequencing. Two patients were identified based on their phenotype. All patients were males. The mean age at diagnosis was 78.7 years. In two patients, the ocular manifestation was the presenting symptom for VEXAS. Seven patients (87.5%) had history of MDS. Systemic inflammation manifestations include: skin rash (n = 5), recurrent fevers (n = 2), relapsing polychondritis (n = 2), pleuritis and pleural effusion (n = 2), poly arteritis nodosa- PAN (n = 1) and thrombophlebitis (n = 1). Seven (87%) patients were presented with periorbital oedema. Three patients showed orbital inflammation. Dacryoadenitis was observed in two patients, and extraocular muscle (EOM) myositis was detected in two patients. Four patients demonstrated ocular inflammation such as: episcleritis, scleritis and anterior uveitis. CONCLUSION: ocular manifestations in VEXAS include orbital inflammation, dacryoadenitis, myositis, uveitis, scleritis, episcleritis and periorbital oedema. We recommend that in old male patients, with history of haematological disorder, presenting with ocular symptom, VEXAS investigation should be taken into consideration.

Inhibitory effect of a neddylation blockade on HTLV-1-infected T cells via modulation of NF-κB, AP-1, and Akt signaling.

Adult T-cell leukemia (ATL), caused by HTLV-1, is the most lethal hematological malignancy. NEDD8-activating enzyme (NAE) is a component of the NEDD8 conjunction pathway that regulates cullin-RING ubiquitin ligase (CRL) activity. HTLV-1-infected T cells expressed higher levels of NAE catalytic subunit UBA3 than normal peripheral blood mononuclear cells. NAE1 knockdown inhibited proliferation of HTLV-1-infected T cells. The NAE1 inhibitor MLN4924 suppressed neddylation of cullin and inhibited the CRL-mediated turnover of tumor suppressor proteins. MLN4924 inhibited proliferation of HTLV-1-infected T cells by inducing DNA damage, leading to S phase arrest and caspase-dependent apoptosis. S phase arrest was associated with CDK2 and cyclin A downregulation. MLN4924-induced apoptosis was mediated by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, MLN4924 inhibited NF-κB, AP-1, and Akt signaling pathways and activated JNK. Therefore, neddylation inhibition is an attractive strategy for ATL therapy. Our findings support the use of MLN4924 in ATL clinical trials.

A Survey on the Expression of the Ubiquitin Proteasome System Components HECT- and RBR-E3 Ubiquitin Ligases and E2 Ubiquitin-Conjugating and E1 Ubiquitin-Activating Enzymes during Human Brain Development.

Human brain development involves a tightly regulated sequence of events that starts shortly after conception and continues up to adolescence. Before birth, neurogenesis occurs, implying an extensive differentiation process, sustained by changes in the gene expression profile alongside proteome remodeling, regulated by the ubiquitin proteasome system (UPS) and autophagy. The latter processes rely on the selective tagging with ubiquitin of the proteins that must be disposed of. E3 ubiquitin ligases accomplish the selective recognition of the target proteins. At the late stage of neurogenesis, the brain starts to take shape, and neurons migrate to their designated locations. After birth, neuronal myelination occurs, and, in parallel, neurons form connections among each other throughout the synaptogenesis process. Due to the malfunctioning of UPS components, aberrant brain development at the very early stages leads to neurodevelopmental disorders. Through deep data mining and analysis and by taking advantage of machine learning-based models, we mapped the transcriptomic profile of the genes encoding HECT- and ring-between-ring (RBR)-E3 ubiquitin ligases as well as E2 ubiquitin-conjugating and E1 ubiquitin-activating enzymes during human brain development, from early post-conception to adulthood. The inquiry outcomes unveiled some implications for neurodevelopment-related disorders.

Ginkgolic acid inhibits the expression of SAE1 and induces ferroptosis to exert an anti-hepatic fibrosis effect.

BACKGROUND: Finding a drug for early intervention in the hepatic fibrosis process has important clinical significance. Previous studies have suggested SUMOylation as a potential target for intervention in hepatic fibrosis. However, the role of SAE1, a marker of SUMOylation, in hepatic fibrosis is unknown. Additionally, whether ginkgolic acid (GA), a SUMOylation inhibitor, inhibits hepatic fibrosis by inhibiting SUMO1-activating enzyme subunit 1 (SAE1) should be further investigated. METHODS: Liver tissues of patients with hepatic cirrhosis and a rat model of hepatic fibrosis constructed with CCl4 (400 mg/kg, twice weekly) or TAA (200 mg/kg, twice weekly) were selected, and the degree of hepatic fibrosis was then evaluated using H&E, Sirius red, and Masson's trichrome staining. After knockdown or overexpression of SAE1 in hepatic stellate cells, the expression levels of ferroptosis and hepatic fibrosis markers were measured in vitro. After intervention with a ferroptosis inhibitor, the expression levels were again measured in vivo and in vitro. RESULTS: We first demonstrated that SAE1 increased in patients with hepatic cirrhosis. Subsequently, testing of the rat hepatic fibrosis model confirmed that GA reduced the expression of SAE1 and improved hepatic fibrosis in rats. Then, we used hepatic stellate cell lines to confirm in vitro that GA inhibited SAE1 expression and induced ferroptosis, and that overexpression of SAE1 or inhibition of ferroptosis reversed this process. Finally, we confirmed in vivo that GA induced ferroptosis and alleviated the progression of hepatic fibrosis, while inhibiting ferroptosis also reversed the progression of hepatic fibrosis in rats. CONCLUSION: SAE1 is a potential anti-fibrotic target protein, and GA induces ferroptosis of hepatic stellate cells by targeting SAE1 to exert an anti-hepatic fibrosis effect, which lays an experimental foundation for the future clinical application of its anti-hepatic fibrosis effect.

ROS-mediated up-regulation of SAE1 by Helicobacter pylori promotes human gastric tumor genesis and progression.

Helicobacter pylori (H. pylori) is a major risk factor of gastric cancer (GC). The SUMO-activating enzyme SAE1(SUMO-activating enzyme subunit 1), which is indispensable for protein SUMOylation, involves in human tumorigenesis. In this study, we used the TIMER and TCGA database to explore the SAE1 expression in GC and normal tissues and Kaplan-Meier Plotter platform for survival analysis of GC patients. GC tissue microarray and gastric samples from patients who underwent endoscopic treatment were employed to detect the SAE1expression. Our results showed that SAE1 was overexpressed in GC tissues and higher SAE1 expression was associated with worse clinical characteristics of GC patients. Cell and animal models showed that H. pylori infection upregulated SAE1, SUMO1, and SUMO2/3 protein expression. Functional assays suggested that suppression of SAE1 attenuated epithelial-mesenchymal transition (EMT) biomarkers and cell proliferation abilities induced by H. pylori. Cell and animal models of ROS inhibition in H. pylori showed that ROS could mediate the H. pylori-induced upregulation of SAE1, SUMO1, and SUMO2/3 protein. RNA sequencing was performed and suggested that knockdown of SAE1 could exert an impact on IGF-1 expression. General, increased SUMOylation modification is involved in H. pylori-induced GC.