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LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages

Ommar Omarjee 1, 2 Anne-Laure Mathieu 1, 2 Gaëlle Quiniou 1 Marion Moreews 1 Michelle Ainouze 1 Cécile Frachette 2, 3 Isabelle Melki 4, 5 Cécile Dumaine 4 Mathieu Gerfaud-Valentin 6 Agnès Duquesne 7 Tilmann Kallinich 8 Eda Tahir Turanli 9, 10 Christophe Malcus 2, 7 Sébastien Viel 2, 7 Rémi Pescarmona 2, 7 Sophie Georgin-Lavialle 11, 12, 13, 14 Yvan Jamilloux 1, 6 Jean-Paul Larbre 2, 7 Guillaume Sarrabay 15 Flora Magnotti 1 Gillian I Rice 16 Francoise Bleicher 17 Jonathan Reboulet 17 Samir Merabet 17 Thomas Henry 1 Yanick J Crow 18, 19 Mathias Faure 1, 2 Thierry Walzer 1, 2 Alexandre Belot 2, 1, 3 
Abstract : 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.
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Ommar Omarjee, Anne-Laure Mathieu, Gaëlle Quiniou, Marion Moreews, Michelle Ainouze, et al.. LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages. Journal of Experimental Medicine, Rockefeller University Press, 2021, 218 (3), pp.e20201006. ⟨10.1084/jem.20201006⟩. ⟨hal-03355059⟩

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