DeCure for Proteasome-associated autoinflammatory syndrome 5
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for proteasome-associated autoinflammatory syndrome 5 — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleProteasome-associated autoinflammatory syndrome 5 maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for proteasome-associated autoinflammatory syndrome 5 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
proteasome 20S subunit beta 10 (PSMB10) — PSMB10 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 1rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6E5B · 2.77 Å · ligand [(1R)-3-methyl-1-[[1-[2-[(2,3,4-trimethoxyphenyl)carbonylamino]ethyl]-1,2,3-triazol-4-yl]carbonylamino]butyl]-tris(oxidanyl)boron (HUJ). Experimental structure, not a prediction.
What the evidence adds up to
Proteasome-associated autoinflammatory syndrome 5 is one of the disorders caused by genetic mutations in proteasome subunits, collectively termed proteasomopathies. A 2022 review notes that most proteostasis disorders, including proteasomopathies, exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and initiation of innate immune responses. The review focuses on how cells sense proteostasis perturbations as danger signals in sterile inflammation, but provides no patient-level data on syndrome 5 specifically.
A 2025 study used a mouse model with a mutation in β5i (Psmb8) combined with T-cell-specific β5 (Psmb5) deficiency, called KIKO mice. These mice showed severe loss of mature T cells in the spleen but not in the thymus, with reduced proteasome activity and accumulation of ubiquitinated proteins. CD4+ T cells from KIKO mice had impaired proliferative activity with cell cycle arrest in G0/G1 phase after T cell receptor engagement, and underwent rapid apoptosis. Treatment with the caspase inhibitor Z-VAD-FMK rescued cell viability. Proteasome dysfunction induced apoptosis without affecting mitochondrial functions or endoplasmic reticulum stress responses. The authors state this provides insight into immunodeficiency in PRAAS patients, but the study is in mice, not humans.
A 2020 review of autoinflammatory dermatoses notes that not all patients respond to IL‑1 beta inhibition, and that several autoinflammatory diseases are associated with mutations in proteasome-immunoproteasome components. These diseases are mostly hereditary and usually begin in childhood, but the review offers no specific outcomes for syndrome 5. What is still missing: human clinical data for syndrome 5, any trial testing a drug in patients with this specific mutation, and patient stratification to identify who might benefit from which immune pathway inhibition.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Cells · 2022 · 28 citations · open access
Proteostasis Perturbations and Their Roles in Causing Sterile Inflammation and Autoinflammatory Diseases
AbstractProteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or degradation. Over the last two decades, an increasing number of disorders caused by proteostasis perturbations have been identified. Depending on their molecular etiology, such diseases may be classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most-if not all-of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses. In this review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and summarize current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide insights into the complex and multiple facets of sterile inflammation.
Pediatric Hematology/Oncology and Immunopathology · 2019 · 3 citations · open access
Clinical case of proteasome-associated autoinflammatory syndrome-2 (PRAAS2)
AbstractThis article describes clinical case of a child with proteasome-associated autoinflammatory syndrome-2 (PRAAS2). First two cases in unrelated boys were described in July, 2018 by M. Cecilia Poli, Frederic Ebstein. We describe another case of PRAAS2. Mutations of the POMP-gene underlie PRAAS2 pathogenesis, causing defects of the POMP protein which plays important role in proteasomes maturation and leads to the clinical symptoms observed in three described cases. We also provide a short PRAAS2 background description, as well as key pathogenesis components, clinical findings description and analysis of three known PRAAS2 cases. Parents gave their consent to use personal data, including photos for clinical research and publications.
International Immunology · 2025 · 2 citations · open access
Proteasome dysfunction in T cells causes immunodeficiency via cell cycle disruption and apoptosis
AbstractProteasomes are essential molecular complexes that regulate intracellular protein homeostasis by selectively degrading ubiquitinated proteins. Genetic mutations in proteasome subunits lead to proteasome-associated autoinflammatory syndromes (PRAAS) characterized by autoinflammation, partial progressive lipodystrophy, and, in certain cases, immunodeficiency. However, the molecular mechanisms by which proteasome dysfunction results in these phenotypes remain unclear. Here, we established a mouse model carrying a mutation in β5i (encoded by Psmb8) along with T-cell-specific β5 (encoded by Psmb5) deficiency (KIKO mice). The KIKO mice presented severe loss of mature T cells in the spleen but not in the thymus, with reduced proteasome activity leading to the accumulation of ubiquitinated proteins. The CD4+ T cells of KIKO mice presented impaired proliferative activity with cell cycle arrest in the G0/G1 phase following T cell receptor (TCR) engagement. T cells from KIKO mice underwent rapid cell death through apoptosis, as treatment of T cells with the caspase inhibitor Z-Val-Ala-Asp(Ome)-fluoromethylketone (Z-VAD-FMK) rescued cell viability. Moreover, proteasome dysfunction induced apoptosis in T cells without affecting either mitochondrial functions or endoplasmic reticulum (ER) stress responses. Thus, our data provide insight into the molecular mechanisms underlying not only immunodeficiency in PRAAS patients but also T-cell deficiency associated with other disorders.
BORIS (University Library Bern) · 2020 · 1 citations · open access
[Pathophysiology of autoinflammatory dermatoses].
AbstractAutoinflammation leads to inflammation that mostly occurs without any clinically obvious reason. It can be so severe that organ damage with relevant tissue damage occurs. Inflammasomes are the drivers of autoinflammation. Although IL‑1 beta and the inflammasomes as its critical regulators are very important in autoinflammation, not all patients respond to inhibition of this signalling pathway. Several autoinflammatory diseases were associated with mutations in proteasome-immunoproteasome components. Autoinflammatory diseases caused by highly relevant genetic variants are mostly hereditary. Usually in childhood but not always. The coming years will show whether inflammatory dermatoses will be increasingly treated with suppression of the innate immune system in addition to inhibition of adaptive immunity.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
