ArticleProceedings of the National Academy of Sciences of the United States of America2019
A folding switch regulates interleukin 27 biogenesis and secretion of its α-subunit as a cytokine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- Discordant Interleukin-27 (IL-27) Subunit Transcription in Human Sepsis Exposes a Molecular-Attribution Gap.Biomedicines · 2026Article
- Recent Insights Into Targeting Interleukin-27 in Coronary Artery Disease.Journal of cardiovascular translational research · 2025Review
- The biology of interleukin-6 family cytokines is regulated by glycosylation.The Biochemical journal · 2025Review
- Integrating Transcriptomic and Proteomic Data: IL-27B as a Key Protein in the Development of Septic Cardiomyopathy-A Retrospective Study.Immunity, inflammation and disease · 2025Article
- IL-27 elicits a cytotoxic CD8Nature · 2025Article
- Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Immunoliposome-based targeted delivery of the CRISPR/Cas9gRNA-IL30 complex inhibits prostate cancer and prolongs survival.Experimental & molecular medicine · 2024Article
- IL-27 expression regulation and its effects on adaptive immunity against viruses.Frontiers in immunology · 2024Review
- IL-27 as a novel biomarker for pruritus in nodular prurigo and bullous pemphigoid.Frontiers in immunology · 2024Article
- Human interleukin-12α and EBI3 are cytokines with anti-inflammatory functions.Science advances · 2023Article
- Inactivation of interleukin-30 in colon cancer stem cells via CRISPR/Cas9 genome editing inhibits their oncogenicity and improves host survival.Journal for immunotherapy of cancer · 2023Article
- Cell type specific IL-27p28 (IL-30) deletion in mice uncovers an unexpected regulatory function of IL-30 in autoimmune inflammation.Scientific reports · 2023Article
- Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27.Cell reports · 2022Article
- CRISPR/Cas9-mediated deletion of Interleukin-30 suppresses IGF1 and CXCL5 and boosts SOCS3 reducing prostate cancer growth and mortality.Journal of hematology & oncology · 2022Article
- Dendritic cell-derived IL-27 p28 regulates T cell program in pathogenicity and alleviates acute graft-versus-host disease.Signal transduction and targeted therapy · 2022Article
- Article
- A high-throughput predictive method for sequence-similar fold switchers.Biopolymers · 2021Article
- Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome.Journal for immunotherapy of cancer · 2021Article
- IL-30Experimental & molecular medicine · 2021Review
- Interleukin-27 and Its Diverse Effects on Bacterial Infections.Frontiers in immunology · 2021Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A common design principle of heteromeric signaling proteins is the use of shared subunits. This allows encoding of complex messages while maintaining evolutionary flexibility. How cells regulate and control assembly of such composite signaling proteins remains an important open question. An example of particular complexity and biological relevance is the interleukin 12 (IL-12) family. Four functionally distinct αβ heterodimers are assembled from only five subunits to regulate immune cell function and development. In addition, some subunits act as independent signaling molecules. Here we unveil key molecular mechanisms governing IL-27 biogenesis, an IL-12 family member that limits infections and autoimmunity. In mice, the IL-27α subunit is secreted as a cytokine, whereas in humans only heterodimeric IL-27 is present. Surprisingly, we find that differences in a single amino acid determine if IL-27α can be secreted autonomously, acting as a signaling molecule, or if it depends on heterodimerization for secretion. By combining computer simulations with biochemical experiments, we dissect the underlying structural determinants: a protein folding switch coupled to disulfide bond formation regulates chaperone-mediated retention versus secretion. Using these insights, we rationally change folding and assembly control for this protein. This provides the basis for a more human-like IL-27 system in mice and establishes a secretion-competent human IL-27α that signals on its own and can regulate immune cell function. Taken together, our data reveal a close link between protein folding and immunoregulation. Insights into the underlying mechanisms can be used to engineer immune modulators.
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