Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.
LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages
Disclosures: S. Georgin-Lavialle reported personal fees from SOBI, non-financial support from Novartis, and personal fees from BMS outside the submitted work. F. Bleicher reported a patent to FR1655539 pending. J. Reboulet reported a patent to FR1655539 issued. S. Merabet reported a patent to FR1655539 pending. T. Henry reported personal fees from SOBI and grants from SOBI outside the submitted work. No other disclosures were reported.
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Ommar Omarjee, Anne-Laure Mathieu, Gaëlle Quiniou, Marion Moreews, Michelle Ainouze, Cécile Frachette, Isabelle Melki, Cécile Dumaine, Mathieu Gerfaud-Valentin, Agnès Duquesne, Tilmann Kallinich, Eda Tahir Turanli, Christophe Malcus, Sébastien Viel, Rémi Pescarmona, Sophie Georgin-Lavialle, Yvan Jamilloux, Jean-Paul Larbre, Guillaume Sarrabay, Flora Magnotti, Gillian I. Rice, Francoise Bleicher, Jonathan Reboulet, Samir Merabet, Thomas Henry, Yanick J. Crow, Mathias Faure, Thierry Walzer, Alexandre Belot; LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages. J Exp Med 1 March 2021; 218 (3): e20201006. doi: https://doi.org/10.1084/jem.20201006
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