The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease

Liu, Zhihua; Lee, Jinwoo; Krummey, Scott M.; Lu, Wei; Cai, Huaibin; Lenardo, Michael J.

doi:10.1038/ni.2113

Cited by 327 publications

(355 citation statements)

References 47 publications

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“…Finally, toll‐like receptor 4 stimulation was able to increase LRRK2 expression and phosphorylation in primary rat microglia 158. LRRK2 was described as a negative regulator of nuclear factor of activated T cells (NFAT), a protein involved in transcriptional regulation in T cells, macrophages, dendritic cells and neutrophils 162; reinforcing the hypothesis that LRRK2 may have a precise role in the immune system because of the peculiar interaction partners through which it can exert tissue‐specific functions. The pathological implications of these observations are intriguing in two ways.…”

Section: Lrrk2 and The Immune Systemmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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Section: Lrrk2 and The Immune Systemmentioning

confidence: 99%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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“…RCAN1 can interact directly with calcineurin in the cytosol to inhibit the phosphatase activity of the protein required for the dephosphorylation and nuclear translocation of NFAT (17,19,24). NFAT activation has been implicated in the function of a wide variety of immune cells, including T cells (25), B cells (26), mast cells (27), NK cells (28), and macrophages (29), where it induces various cytokines, including IL-2 (25), IL-3 (30), IL-4 (31), IL-5 (32), IL-6 (33), TNF (34), and GM-CSF (35), among others.…”

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confidence: 99%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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Respiratory tract infection with Pseudomonas aeruginosa is a common cause of hospitalization in immune-compromised individuals. However, the molecular mechanisms involved in the immune response to P. aeruginosa lung infection remain incompletely defined. In this study, we demonstrate that the regulator of calcineurin 1 (RCAN1) is a central negative regulator of inflammation in a mouse model of acute bacterial pneumonia using the opportunistic bacterial pathogen P. aeruginosa. RCAN1-deficient mice display greatly increased mortality following P. aeruginosa lung infection despite enhanced neutrophil recruitment and bacterial clearance. This mortality is associated with higher systemic levels of proinflammatory cytokines in RCAN1-deficient animals. These aberrant inflammatory responses coincide with increased transcriptional activity of proinflammatory RCAN1-target proteins NFAT and NF-κB. In addition, we reveal a novel regulatory role for RCAN1 in the ERK/STAT3 pathway both in vitro and in vivo, suggesting that aberrant STAT3 activity may significantly contribute to delayed resolution of inflammatory responses in our model. Together, these findings demonstrate that RCAN1 is a potent negative regulator of inflammation during respiratory tract infections.

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“…Deficiency of both NFATc1 and NFATc2 severely attenuates the expression of IL-2, confirming the critical role of NFATs in regulating IL-2 expression (9). In resting T cells, NFATs are phosphorylated and retained in cytoplasm by the NRON complex, which consists of a backbone of noncoding RNA called noncoding RNA repressor of NFAT (NRON) and several proteins, including Tnpo1, Iqgap1, chromosome segregation 1-like (Cse1l), protein phosphatase 2, regulatory subunit A, alpha (Ppp2r1a), and Psmd11 (10)(11)(12). The NRON complex serves as a cytoplasmic trap of NFAT.…”

mentioning

confidence: 94%

Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter

Tsao

Tai

Tseng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.E 26 transformation-specific sequence 1 (Ets-1) is the founding member of the ETS family of transcription factors (1, 2); it is expressed mainly in lymphoid cells and plays multiple roles in regulating the development and function of these cells. Ets-1-deficient (KO) Th1 cells produce very little IL-2 (3). However, it is still unclear whether Ets-1 is also critical for the expression of IL-2 in human Th cells and how Ets-1 promotes the expression of IL-2.The transcriptional regulation of IL-2 has been characterized (4, 5). One of the positive regulators of IL-2 expression is the nuclear factor of activated T-cells (NFAT) family of transcription factors, which contains five members (6, 7). The promoter of the IL-2 gene contains five consensus binding sequences of NFAT (8). Deficiency of both NFATc1 and NFATc2 severely attenuates the expression of IL-2, confirming the critical role of NFATs in regulating IL-2 expression (9). In resting T cells, NFATs are phosphorylated and retained in cytoplasm by the NRON complex, which consists of a backbone of noncoding RNA called noncoding RNA repressor of NFAT (NRON) and several proteins, including Tnpo1, Iqgap1, chromosome segregation 1-like (Cse1l), protein phosphatase 2, regulatory subunit A, alpha (Ppp2r1a), and Psmd11 (10-12). The NRON complex serves as a cytoplasmic trap of NFAT. T-cell antigen receptor (TCR) signals and dephosphorylation of NFAT lead to the release of NFAT from the NRON complex. Free dephosphorylated NFAT is then translocated into the nucleus and transactivates IL-2 and many other genes. However, the detailed mechanism regulating the assembly/disassembly of the NRON complex and cytoplasmic/nuclear translocation of NFAT is still not fully understood.B lymphocyte-i...

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The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease

Cited by 327 publications

References 47 publications

Cellular processes associated with LRRK2 function and dysfunction

Cellular processes associated with LRRK2 function and dysfunction

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter

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