E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury

Abstract

The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappaB (NF-kappaB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.

E3 Ubiquitin Ligase Tripartite Motif 38 Negatively Regulates TLR-Mediated Immune Responses by Proteasomal Degradation of TNF Receptor-Associated Factor 6 in Macrophages

“…K63-linked ubiquitination of TRAF6, RIP1, and IKK-g is essential for the activation of TLR signaling (11)(12)(13). In contrast, K48-linked ubiquitination can promote the degradation of target molecules through proteasome, therefore limiting innate immune response (14)(15)(16)(17). Protein ubiquitination requires the sequential action of three enzymes: an ubiquitinactivating enzyme (E1), an ubiquitin-conjugating enzyme (E2), and an ubiquitin ligase (E3).…”

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

“…Moreover, perturbed thymocyte signalling does not depend on the TKB domain of c-Cbl, as a TKB knock-in did not rescue the phenotype (Thien et al, 2003). In contrast, Cbl-b ablation results in an impaired immunological tolerance induction and animals succumb to spontaneous and/or induced autoimmune diseases with widespread inflammatory organ (pancreas, lung) and tissue (adipose) damage (Bachmaier et al, , 2007Hirasaka et al, 2007). Importantly, Cbl-b-null mice are able to reject multiple types of tumours spontaneously (Chiang et al, 2007;Loeser et al, 2007).…”

Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance

“…27,28 In addition to TRAF6 and TRAF3, several other E3 ubiquitin ligases have been implicated in the positive or negative regulation of TLR/IL-1R signaling. [29][30][31][32] In particular, a recent study suggests a role for the cIAP1 and cIAP2 in the regulation of MyD88-dependent TLR signaling. 31 cIAPs are RING E3s with both K63 and K48 types of ubiquitin ligase activity.…”