SHP Gains Citizenship of the AMPK Kingdom

RESEARCH HIGHLIGHT

SHP gains citizenship of the AMPK kingdom

Hun-Taeg Chung

Cellular & Molecular Immunology (2011) 8, 450–452; doi:10.1038/cmi.2011.39; published online 19 September 2011

arious cytokines and chemokines resulting in the induction of proinflammatory cholesterol metabolism. Yuk and collea- V are produced as a result of signaling genes.1 gues3 demonstrated that SHP associates through innate immune receptors. Such sig- TLR signaling must be tightly regulated with NF-kB in the cytosol of resting cells, naling is initiated by host–pathogen interac- because imbalances between activation and as well as interferes with the ubiquitination tions in which the host’s germline-encoded inhibition of the immune system could cause of the upstream signaling protein TRAF6 in pattern recognition receptors, including detrimental and inappropriate inflammatory lipopolysaccharide (LPS)-stimulated cells. Toll-like receptors (TLRs), recognize con- responses. To date, more than two dozen According to their study, LPS induces served microbial structures termed patho- negative regulatory molecules have been Ca21 influx, which activates the Ca21/cal- gen-associated molecular patterns. reported to attenuate TLR signaling at mul- modulin-dependent protein kinase kinase-b. TLRs are broadly distributed in immune tiple levels. This, in turn, activates AMP-activated kinase cells and are responsible for eliciting innate It is well established that extracellular sol- (AMPK). Abundant expression of SHP results responses and enhancing adaptive immun- uble decoy receptors such as soluble TLR4 from the binding of USF1 to the SHP pro- ity to pathogens. The 12 members of the and TLR2 could be effective in blocking moterinresponsetoAMPKsignaling.The TLR family in mammals are character- TLR signaling. At the membrane level, there triggering of the receptor STK (a homolog of ized by an extracelluar leucine-rich repeat are several regulators, including ST2, RON in humans) by macrophage-stimulating domain and an intracellular Toll/IL-1 recep- SIGIRR, TRAILR, TRIAD3A and carbon protein mimics the LPS-induced expression of tor domain. monoxide (CO), which suppress TLR func- SHP via an LKB1–AMPK–USP1-dependent TLR signaling is initiated by ligand bind- tion. In the case of TRIAD3A, the express- pathway, which also results in inhibition of ing, receptor subunit dimerization and con- ion of TLRs is reduced through the TLR signaling (Figure 1). formational changes in the receptor, followed ubiquitination and degradation pathway. In January, 2011 issue of American Journal of by the recruitment of Toll/IL-1 recep- There are many negative regulators that Physiology—Heart and Circulatory Physiology, tor domain-containing adaptors, including affect TLR signaling intracellularly, includ- Liu and colleagues4 reported that the in vitro MyD88 and TRIF. MyD88 then recruits ing MyD88, IRAKM, SOCS1, NOD2, PI3K, or in vivo activation of AMPK stimulates heme IL-1 receptor-associated kinase (IRAK)-4 TOLLIP and A20. A20, for example, is oxygenase (HO)-1 gene expression in endothe- and IRAK-1 through a homophilic inter- known to block TLR signaling by deubiqui- lial cells, via the Nrf2/antioxidant responsive action between the death domains. After tination of TRAF6. By contrast, the death element signaling pathway. The AMPK activa- association with MyD88, IRAK-1 is phos- domain-containing protein MyD88 and the tors, AICAR and A-769662, stimulate a con- phorylated by activated IRAK-4 and then nuclear receptor Nur77 regulate TLR signaling centration- and time-dependent increase in associates with tumor-necrosis factor recep- by inducing apoptosis. In addition, anti- HO-1 protein and mRNA expression. The tor-associated factor 6 (TRAF6), which acts inflammatory cytokines such as transforming induction of HO-1 was also observed in rat as a ubiquitin-protein ligase (E3). TRAF6 growth factor-b and IL-1 can downregulate carotid arteries after the in vivo application of catalyzes the formation of the K63-linked the expression and function of TLRs.2 AICAR, and this induction is blocked by the polyubiquitin chain on TRAF6 itself and In August, 2011 issue of Nature Immunology, AMPKinhibitorcompoundCandbysilencing on NEMO, together with a ubiquitin conjug- Yuk and colleagues3 identified a previously AMPK-a1/2 (Figure 1). ating (E2) complex of UBC13 and UEV1A. unknown function for the orphan nuclear HO-1 degrades heme into CO, iron and This ubiquitination activates TAK1, TAB1, receptor small heterodimer partner (SHP) biliverdin. The anti-inflammatory properties TAB2 and the TAB3 complex. TAK1 then as a negative regulator of TLR signaling and of the HO-1/CO system have been demon- phosphorylates IkB kinase-b and map kinase the subsequent NF-kB activation. SHP is a strated in HO-1 knockout mice and in a kinase 6, modulating the activation of NF-kB transcriptional repressor and exerts its regu- human case of genetic HO-1 deficiency, both and mitogen-activated protein kinases, and latory functions in three ways: DNA binding of which showed severe inflammation. HO-1- derived CO inhibits TLR-4 signaling via School of Biological Sciences, University of Ulsan, Meta- inhibition of the nuclear receptor (NR); coac- Inflammation Basic Research Laboratory, Ulsan, Korea tivator competition with the NR; or recruit- blocking both the translocation of TLR-4 to Correspondence: Dr HT Chung, School of Biological ment of a corepressor to the NR, through lipid rafts and the interaction of TLR-4 with Sciences, University of Ulsan, Meta-Inflammation Basic protein–protein interaction with other NRs. caveolin.5 Research Laboratory, Ulsan, Korea. E-mail: [email protected] SHP comprises only a ligand-binding domain AMPK is a crucial regulator of energy Received 30 July 2011; accepted 5 August 2011 and is intricately involved in glucose and metabolism homeostasis at the cellular and Research highlight 451

threonine kinase 11 (LKB1), Ca21/calmodulin- dependent protein kinase kinase-b and transforming growth factor-b-activated kinase 1. The downstream substrates of AMPK are typically energy metabolism enzymes and proteins that are involved in transcriptional regulation. AMPK signaling either stimulates energy production or inhibits energy-con- suming pathways. The AMPK signaling system maintains metabolic homeostasis during adipose tissue stress that is caused by chronic nutrient overload and positive energy balance.6 The accumulation of lipids in adipocytes was shown to stimulate the innate immune system, leading to the secretion of proinflammatory cytokines. Several recent reports have demonstrated that certain TLRs, for example, TLR2 and TLR4, also respond to endogenous ligands such as heat shock proteins, high mobility group box-1 and dietary saturated fatty acids.7 Recently, the activation of TLR signaling has been recognized as an activator of obesity-induced inflammation. Obesity- induced low-grade chronic inflammation has a crucial role in the development of metabolic syndrome.8 There are emerging results indicating that AMPK signaling can inhibit inflammatory responses via downstream tar- gets of AMPK: for example, SIRT1, PGC1a, p53 and FoxO factors.9 AMPK can also inhibit endoplasmic reticulum stress and oxidative stress, which are involved in obesity-induced inflammation.8 Several negative regulators, including SHP and CO, which target components of the TLR signaling pathway, are produced through the activation of AMPK (Figure 1). So AMPK can be consid- ered a nodal master regulator of inflammation that originates from outside or inside the body.

COMPETING FINANCIAL INTERESTS Figure 1 Upstream and downstream AMPK signaling pathways that negatively regulate NF-kB activation and The author declares no competing financial suppress inflammatory responses. AMPK is activated by several hormones, many phytochemicals, certain interests. drugs (for example, metformin) and physical exercise. Obesity and hyperglycemia reduce the expression of AMPK. But Yuk et al.3 showed that LPS, which strongly activates NF-kB via TLR signaling, induced SHP transcription via aCaMKKb–AMPK–USP1-dependent signaling pathway and that newly produced SHP inhibited NF-kB in a negative feedback loop. MSP mimicked LPS in that it induced the expression of SHP via an LKB1–AMPK–USP1-dependent pathway, attenuating LPS-induced NF-kB activation. Once 1 Kumar H, Kawai T, Akira S. Pathogen recognition by AMPK has been activated, it stimulates SIRT1, PGC1a, FoxO and p53, which could attenuate NF-kB activa- the innate immune system. Int Rev Immunol 2011; tion. Liu et al.4 showed that AMPK, via the Nrf2/ARE pathway, induced the HO-1/CO system, which reduced 30: 16–34. cellular stress and inhibited TLR signaling pathways, resulting in the suppression of NF-kB activation. AMPK 2 Liew FY, Xu D, Brint EK, O’Neil LA. Negative regulation of Toll-like receptor-mediated immune responses. Nat can ameliorate inflammatory responses via various direct and indirect anti-inflammatory signaling pathways. Rev Immunol 2005; 5: 446–455. H #, activation; , inhibition. AMPK, AMP-activated kinase; ARE, antioxidant responsive element; CaMKKb, 3 Yuk JM, Shin DM, Lee HM, Kim JJ, Kim SW, Jin HS 21 Ca /calmodulin-dependent protein kinase kinase-b; HO-1/CO, heme oxygenase-1/carbon monoxide; LPS, et al. The orphan nuclear receptor SHP acts as a lipopolysaccharide; MSP, macrophage-stimulating protein; SHP, small heterodimer partner; TLR, Toll-like negative regulator in inflammatory signaling receptor. triggered by Toll-like receptors. Nat Immunol 2011; 12: 742–751. 4 Liu XM, Peyton KJ, Shebib AR, Wang H, Korthuis RJ, Durante W. Activation of AMPK stimulates heme whole organism levels. AMPK is a serine/ complex is activated by the allosteric regu- oxygenase-1 gene expression and human endothelial threonine kinase and consists of a heterotri- lation of increased AMP concentration and cell survival. Am J Physiol Heart Circ Physiol 2011; 300: H84–H93. meric complex, including a catalytic a-subu- by the phophorylation of the a-subunit 5 Paine A, Eiz-Vesper B, Blasczyk R, Immenschuh S. Sig- nit and regulatory b- and c-subunits. This (at Thr 172) via the upstream kinases serine/ naling to heme oxygenase-1 and its anti-inflammatory

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