MARCH1 E3 Ubiquitin Ligase Dampens the Innate Inflammatory Response by Modulating Monocyte Functions in Mice

Abstract

Ubiquitination was recently identified as a central process in the pathogenesis and development of numerous inflammatory diseases, such as obesity, atherosclerosis, and asthma. Treatment with proteasomal inhibitors led to severe side effects because ubiquitination is heavily involved in a plethora of cellular functions. Thus, new players regulating ubiquitination processes must be identified to improve therapies for inflammatory diseases. In addition to their role in adaptive immunity, endosomal MHC class II (MHCII) molecules were shown to modulate innate immune responses by fine tuning the TLR4 signaling pathway. However, the role of MHCII ubiquitination by membrane associated ring-CH-type finger 1 (MARCH1) E3 ubiquitin ligase in this process remains to be assessed. In this article, we demonstrate that MARCH1 is a key inhibitor of innate inflammation in response to bacterial endotoxins. The higher mortality of March1 mice challenged with a lethal dose of LPS was associated with significantly stronger systemic production of proinflammatory cytokines and splenic NK cell activation; however, we did not find evidence that MARCH1 modulates LPS or IL-10 signaling pathways. Instead, the mechanism by which MARCH1 protects against endotoxic shock rests on its capacity to promote the transition of monocytes from Ly6C to Ly6C Moreover, in competitive bone marrow chimeras, March1 monocytes and polymorphonuclear neutrophils outcompeted wild-type cells with regard to bone marrow egress and homing to peripheral organs. We conclude that MARCH1 exerts MHCII-independent effects that regulate the innate arm of immunity. Thus, MARCH1 might represent a potential new target for emerging therapies based on ubiquitination reactions in inflammatory diseases.

MARCH1 encourages tumour progression of hepatocellular carcinoma via regulation of PI3K‐AKT‐β‐catenin pathways

“…8 Ubiquitination was recently identified as an important and specific process, participating in several protein degradation and cell signalling pathways through the close cooperation of three enzymes: the ubiquitin-activating enzyme E1, the ubiquitin-conjugating enzyme E2 and the ubiquitin-ligase enzyme E3. 8 Ubiquitination was recently identified as an important and specific process, participating in several protein degradation and cell signalling pathways through the close cooperation of three enzymes: the ubiquitin-activating enzyme E1, the ubiquitin-conjugating enzyme E2 and the ubiquitin-ligase enzyme E3.…”

“…Membrane-associated RING-CH-1 (MARCH1) is a member of the membrane-associated RING-CH (MARCH) family of E3 ubiquitin ligase and a negative regulator of adaptive immunity. 8 Ubiquitination was recently identified as an important and specific process, participating in several protein degradation and cell signalling pathways through the close cooperation of three enzymes: the ubiquitin-activating enzyme E1, the ubiquitin-conjugating enzyme E2 and the ubiquitin-ligase enzyme E3. 9,10 MARCH1 is primarily expressed in antigen-presenting cells and mediates the ubiquitination of MHCII and CD86 in dendritic cells (DCs) to control DC-mediated Treg cells.…”

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

“…These IL-10-regulated genes included SOCS3 and MARCH1 ( Fig. 4 B) with known anti-inflammatory functions (Croker et al, 2003;Galbas et al, 2017;Hunt et al, 2012;Mittal et al, 2015;Wong et al, 2006). Similarly, WT and IL-10RB −/− Mφs showed an almost identical transcriptional response to LPS stimulation with ∼1,050 up-regulated (Table S1) and ∼950 down-regulated genes (Table S2) in both Mφs.…”

“…How IL-10 exerts its anti-inflammatory response is not fully elucidated; our transcriptomic analysis provided some potential clues that warrant further investigation. IL-10 stimulation alone affects the expression of only a few genes in control Mφs, including SOCS3 (Croker et al, 2003;Wong et al, 2006) and MARCH1 (Galbas et al, 2017;Hunt et al, 2012;Mittal et al, 2015) with known anti-inflammatory and Mφ deactivation functions.…”

Autophagy and Ubiquitination in Salmonella Infection and the Related Inflammatory Responses

“…In addition to their action in adaptive immune responses, endosomal MHC class II (MHCII) molecules were proved to regulate innate immunity via sharp tuning the TLR4 signaling pathway. However, MARCH1 E3 Ub ligase exerts an MHCII-independent effect that accommodating the innate immunity based on ubiquitination (Galbas et al, 2017 ). Although AvrA, GogB, SseK3, and SteD are the effectors without enzymatic activity of ubiquitination, they can affect the inflammatory responses by degrading Ub or interacting with different E3 Ub ligases.…”