Molecular mechanisms in rare proteasomopathies
Sophie Wolfgramm1, Flavia Llorente Alvarez1, Franziska G Thiel1
1Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany.
EULAR Rheumatology Open
|June 29, 2026
Summary
Proteasomopathies are rare genetic disorders affecting proteasome function, leading to protein imbalance. Structural modeling innovations can accelerate the diagnosis of these complex interferonopathy-related syndromes.
Area of Science:
- Molecular Biology
- Genetics
- Immunology
Background:
- Proteasomopathies are rare interferonopathy-related syndromes stemming from genetic defects in proteasome assembly or function.
- These defects disrupt ubiquitin-mediated protein degradation, causing protein homeostasis imbalance.
- Known phenotypes include autoinflammatory and neurodevelopmental disorders, sharing molecular hallmarks like protein aggregation and altered interferon signaling.
Purpose of the Study:
- To integrate current knowledge of mammalian proteasome biogenesis.
- To analyze known proteasomopathy-causing variants using structural modeling.
- To discuss how structural modeling can improve diagnostic timelines.
Main Methods:
- Review of mammalian proteasome biogenesis literature.
- Structural modeling of proteasome variants.
- Integration of genetic and structural data.
Main Results:
- Characterization of two distinct proteasomopathy phenotypes (autoinflammatory, neurodevelopmental).
- Identification of shared molecular features across phenotypes (protein aggregation, stress responses, interferon dysregulation).
- Demonstration of structural modeling's potential in understanding disease mechanisms.
Conclusions:
- Proteasome dysfunction underlies diverse clinical syndromes with shared molecular pathology.
- Structural modeling offers a promising avenue for accelerating the diagnosis of proteasomopathies.
- Further research integrating structural and genetic data is crucial for clinical management.
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In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin...
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