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The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity.

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Title: The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity.
Authors: Laurent, Paôline1,2, Chaudhary, Vidyanath1,2, Daqiang Li2, Ah Kioon, Marie Dominique1, Chen Zhang3, Miller, William H.4, Hua Liao4, Gang Lin2,5, Nathan, Carl F.2,6 cnathan@med.cornell.edu, Barrat, Franck J.1,2,6,7 barratf@hss.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 11/25/2025, Vol. 122 Issue 47, p1-12. 21p.
Subjects: Innate lymphoid cells, Proteasomes, Metabolic reprogramming, Reactive oxygen species, Bronchial diseases, Asthma, Immune response, Cell respiration
Abstract: Type 2 innate lymphoid cells (ILC2s) contribute to type 2 immunity but have also been associated with multiple inflammatory diseases, including airway inflammation and asthma. We report that beyond its function of degrading poly-ubiquitinylated proteins, the immunoproteasome (i-20S) is required for the proper function of ILC2s by controlling their mitochondrial capacity. We found that 90% of the catalytic ß subunits of proteasomes in human ILC2s (hILC2s) are the immuno-(ß5i) rather than constitutive (ß5c) isoform. Specific, noncovalent, reversible inhibition of i-20S ß5i (LMP7) in hILC2s induced ROS production, which inhibited aconitase, leading to altered mitochondrial function and reduced levels of ATP. Reprogramming of metabolic status by an LMP7 inhibitor impaired ILC2 activation, without significant cytotoxicity or preventing their recovery. Hence, the selective inhibition of i-20S in ILC2 cells did not kill them but reversibly depleted their ATP, preventing their activation and cytokine secretion. In mice, proteasome inhibition similarly blocked mitochondrial function and ILC2 activation, preventing airway inflammation in response to IL33 and asthma in response to house dust mites. These findings reveal a previously unappreciated linkage between proteasome blockade, central carbon metabolism, and mitochondrial function and identify a strategy to regulate immune cell metabolism in inflammatory diseases. [ABSTRACT FROM AUTHOR]
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Abstract:Type 2 innate lymphoid cells (ILC2s) contribute to type 2 immunity but have also been associated with multiple inflammatory diseases, including airway inflammation and asthma. We report that beyond its function of degrading poly-ubiquitinylated proteins, the immunoproteasome (i-20S) is required for the proper function of ILC2s by controlling their mitochondrial capacity. We found that 90% of the catalytic ß subunits of proteasomes in human ILC2s (hILC2s) are the immuno-(ß5i) rather than constitutive (ß5c) isoform. Specific, noncovalent, reversible inhibition of i-20S ß5i (LMP7) in hILC2s induced ROS production, which inhibited aconitase, leading to altered mitochondrial function and reduced levels of ATP. Reprogramming of metabolic status by an LMP7 inhibitor impaired ILC2 activation, without significant cytotoxicity or preventing their recovery. Hence, the selective inhibition of i-20S in ILC2 cells did not kill them but reversibly depleted their ATP, preventing their activation and cytokine secretion. In mice, proteasome inhibition similarly blocked mitochondrial function and ILC2 activation, preventing airway inflammation in response to IL33 and asthma in response to house dust mites. These findings reveal a previously unappreciated linkage between proteasome blockade, central carbon metabolism, and mitochondrial function and identify a strategy to regulate immune cell metabolism in inflammatory diseases. [ABSTRACT FROM AUTHOR]
ISSN:00278424
DOI:10.1073/pnas.2518190122