An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis

Abstract

Nuclear factor κB (NF-κB)–mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In this study, we demonstrated that ankyrin repeat and suppressor of cytokine signaling box containing 1 (ASB1) is involved in the positive regulation of inflammatory responses by enhancing the stability of TAB2 and its downstream signaling pathways, including NF-κB and mitogen-activated protein kinase pathways. Mechanistically, unlike other members of the ASB family that induce ubiquitination-mediated degradation of their target proteins, ASB1 associates with TAB2 to inhibit K48-linked polyubiquitination and thereby promote the stability of TAB2 upon stimulation of cytokines and lipopolysaccharide (LPS), which indicates that ASB1 plays a noncanonical role to further stabilize the target protein rather than induce its degradation. The deficiency of Asb1 protects mice from Salmonella typhimurium– or LPS-induced septic shock and increases the survival of mice. Moreover, Asb1-deficient mice exhibited less severe colitis and intestinal inflammation induced by dextran sodium sulfate. Given the crucial role of ASB proteins in inflammatory signaling pathways, our study offers insights into the immune regulation in pathogen infection and inflammatory disorders with therapeutic implications.

Ubiquitylation of cyclin C by HACE1 regulates cisplatin‐associated sensitivity in gastric cancer

“…Usually, seven lysine residues and an N‐terminus of ubiquitin are served for protein ubiquitination, including K6, K11, K27, K29, K33, K48, K63 and M1 24 . The role of K48 and K63 is well studied for facilitating or preventing proteasomal degradation of the substrate protein, respectively 34–38 . K11‐linked chains are often accompanied by the K48 counterparts in regulating protein degradation involved in cell mitosis, 39 as well as protein expressions of type 1 interferon 40 and hypoxia‐inducible factors HIF1α and HIF2α 41 .…”

“… 24 The role of K48 and K63 is well studied for facilitating or preventing proteasomal degradation of the substrate protein, respectively. 34 , 35 , 36 , 37 , 38 K11‐linked chains are often accompanied by the K48 counterparts in regulating protein degradation involved in cell mitosis, 39 as well as protein expressions of type 1 interferon 40 and hypoxia‐inducible factors HIF1α and HIF2α. 41 Although Lys11‐linked Ub chains have been regarded as proteasomal signals in cell cycles in APC/C signaling pathway, 42 recent evidence has shown that homotypic K11 linkages do not direct the substrate for proteasomal degradation, instead, the heterotypic K11 linkages are efficient for targeting proteasomal degradation.…”

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

“…The dysfunction or death of these cells are closely involved in sepsis-AKI (22)(23)(24). During the host's defense against infection, macrophages play a central role in innate immunity (25,26), recognizing pathogen-associated molecular patterns (PAMPs) and/or host-derived damage-associated molecular patterns (DAMPs) through pattern recognition receptors (27,28). PAMPs and/or DAMPs released from damaged tissues activate and promote the pro-inflammatory phenotype (M1) of macrophages, leading to the release of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), chemokines and reactive oxygen species (ROS), which cause damage to the kidney tissue (29,30).…”

Investigation of hub gene associated with the infection of Staphylococcus aureus via weighted gene co-expression network analysis

“…According to the ROC curve, ASB1, UBB, and MKRN1 can effectively act as potential diagnostic markers for distinguishing samples of Staphylococcus aureus infection from healthy counterparts. ASB1, a member of the ASB family, acted as a positive regulator of NF-κB– and MAPK-mediated inflammatory signaling pathways [ 39 ]. Appropriate inflammatory response helps immune cells fight microbial infections while excessive inflammatory response can damage tissues and cells [ 40 ].…”

“…Appropriate inflammatory response helps immune cells fight microbial infections while excessive inflammatory response can damage tissues and cells [ 40 ]. The study pointed that ASB1 deficiency protected mice from LPS- or bacteria-induced death by inhibiting inflammation [ 39 ]. Therefore, we speculated that inhibition and down-regulation of ASB1 in the late stage of infection can against the inflammatory injury induced by Staphylococcus aureus .…”