« Our immune system is vital to us and can sometimes overreact causing chronic illnesses, such as for instance rheumatism and allergy. Now, researchers from Umeå University and University of Gothenburg have identified a molecular switch – MYSM1 – that can suppress such an overreaction and avoid inflammation. The study is published in the prestigious Journal Immunity.
“The discovery of MYSM1 is a major milestone in our understanding of how our immune system works, and how its response could be controlled in order to prevent inflammatory diseases such as sepsis,” says Nelson O. Gekara, research leader at MIMS, Molecular Infection Medicine Sweden at Umeå University.
Our innate immune system is activated when our body needs to protect itself against pathogens, for instance bacteria and viruses, as well as for tissue healing. In some people, the immune system overreacts which can cause chronic inflammatory diseases and result in tumour development. The innate immune system is activated by receptors that recognise certain molecular patterns found on microbes or dead cells. These receptors are called pattern-recognition receptors (PRRs).
“Most infectious or inflammatory situations are associated with the simultaneous or sequential activation of multiple PRR pathways. Therefore, it is essential to avert a disproportionate self-destructive immune response in a synchronised fashion once activated. How this is accomplished has been unclear,” says Nelson O. Gekara.
Nelson O. Gekara’s at Umeå University and his doctoral student Swarup Panda are now closing in on a solution. For years, they have been searching for possible genes required for the regulation of the immune system. Together with Professor Jonas A Nilsson at Sahlgrenska Cancer Center at the University of Gothenburg, the Umeå researchers have now identified MYSM1 – a molecule in the cell core (nucleus) of resting cells. For the first time, the researchers are now able to show that during infection or inflammation MYSM1 accumulates outside of the nucleus, in the cytoplasm where it disrupts the function of signalling molecules involved in activation of PRR pathways, thereby terminating inflammation.
“MYSM1 can be said to act like a molecular switch that can turn off several inflammatory pathways. Therefore lack of MYSM1 in animal results in unrestrained activation of the innate immune system, leading to inflammatory diseases” says Nelson O. Gekara.
His research team is now screening for small molecule compounds that are able to modulate the MYSM1 molecule activity. The hope is to find new therapeutics against infections and other inflammatory diseases. »
Swarupa Panda, Jonas A. Nilsson, and Nelson O. Gekara (2015): Deubiquitinase MYSM1 Regulates Innate Immunity through Inactivation of TRAF3 and TRAF6 Complexes. Immunity 43, 1–13, October 20, 2015
- MYSM1 inhibits PRR pathways for pro-inflammatory and type I IFN gene induction
- MYSM1 transiently accumulates in the cytoplasm upon microbial challenge
- MYSM1 interacts with and inactivates TRAF3 and TRAF6 via its SWIRM and MPN domains
- MYSM1 protects against sepsis but renders mice more susceptible to viral infection
« Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response. »
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