LACC1 Required for NOD2-Induced, ER Stress-Mediated Innate Immune Outcomes in Human Macrophages and LACC1 Risk Variants Modulate These Outcomes

Abstract

Highlights d LACC1 localizes to the ER upon PRR stimulation of human macrophages d LACC1 associates with ER-stress sensors and promotes the UPR upon PRR stimulation d LACC1-dependent ER stress is required for PRR-initiated downstream pathways d Common and rare disease-risk variants in LACC1 show a reduction in ER stress

Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2

“…Different findings were reported in studies examining human monocyte-derived macrophages (MDM) [ 32 , 33 ]. One study demonstrates by RNAi-mediated knockdown that thapsigargin-induced ER stress does not require expression of NOD1 or NOD2, either alone or in combination [ 32 ].…”

“…Different findings were reported in studies examining human monocyte-derived macrophages (MDM) [ 32 , 33 ]. One study demonstrates by RNAi-mediated knockdown that thapsigargin-induced ER stress does not require expression of NOD1 or NOD2, either alone or in combination [ 32 ]. Instead, their data revealed that MDP induces an UPR that involves all three branches of the ER stress response mediated by interaction of NOD2, RIP2, and laccase domain containing-1 (LACC1) at the ER membrane [ 32 ].…”

“…One study demonstrates by RNAi-mediated knockdown that thapsigargin-induced ER stress does not require expression of NOD1 or NOD2, either alone or in combination [ 32 ]. Instead, their data revealed that MDP induces an UPR that involves all three branches of the ER stress response mediated by interaction of NOD2, RIP2, and laccase domain containing-1 (LACC1) at the ER membrane [ 32 ]. Another study indicates that a bacterial ligand able to stimulate both NOD1 and NOD2 (M-triDAP) does not induce ER stress when added to MDM alone [ 33 ].…”

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

“…11 The first autoinflammatory disease recognized, FMF, is an inflammasomopathy; other autoinflammatory diseases arise through defects affecting IFN, nuclear factor kappa B (NF-kB), and/or aberrant TNF activity, and miscellaneous mechanisms (Fig 3). [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] New categories of autoinflammatory disease will no doubt emerge over time. Inflammasomopathies and other diseases arising through IL-1-family cytokines…”

LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages

“…Genome-wide association studies had previously associated LACC1 to immune- and bacteria-mediated diseases such as inflammatory bowel diseases and leprosy. Mouse and human studies have suggested multiple roles of LACC1 in fatty acid synthase-mediated de novo lipogenesis ( Cader et al, 2016 ), NOD2-mediated signaling ( Lahiri et al, 2017 ), ER stress ( Huang et al, 2019 ), and, more recently, purine nucleotide cycle ( Cader et al, 2020 ). A common finding in these studies was an impairment of macrophage effector function in terms of production of cytokines and reactive oxygen species in the absence of LACC1, consistent with aberrant host microbial interactions.…”