Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists

Cheng, Kui; Gao, Meng; Godfroy, James I.; Brown, Peter N.; Kastelowitz, Noah; Yin, Hang

doi:10.1126/sciadv.1400139

Cited by 72 publications

(66 citation statements)

References 56 publications

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“…The purified HMGB1 protein was applied to HEK-293 cells overexpressing various human (h) TLRs (HEK-hTLRs). TLR activation was determined by a previously established SEAP signaling assay (Cheng et al, 2015). Interestingly, we obtained significant stimulation of hTLR2, hTLR4 and hTLR5 by full-length rat HMGB1 (Figure 1A) in HEK cells.…”

Section: Resultsmentioning

confidence: 99%

HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

et al. 2016

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SUMMARY Infectious and sterile inflammatory diseases are correlated with increased levels of high mobility group box-1 (HMGB1) in tissues and serum. Extracellular HMGB1 is known to activate toll-like receptors (TLRs) 2, 4 and RAGE (receptor for advanced glycation endproducts) in inflammatory conditions. Here we find that TLR5 is also an HMGB1 receptor that was previously overlooked due to lack of functional expression in the cell lines usually used for studying TLR signaling. HMGB1 binding to TLR5 initiates NF-κB signaling pathway activation in a MyD88-dependent manner, resulting in proinflammatory cytokine production and pain enhancement in vivo. Biophysical and in vitro results highlight an essential role for the C-terminal tail region of HMGB1 in facilitating interactions with TLR5. These results suggest that HMGB1-modulated TLR5 signaling is responsible for pain hypersensitivity.

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Section: Resultsmentioning

confidence: 99%

HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

et al. 2016

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“…Similar methods have led to the discovery of an agonist for the same receptors (110), demonstrating that screening for both agonists and antagonists can be fruitful.…”

Section: Approaches To Targeting Membrane Protein Interactionsmentioning

confidence: 99%

Drugging Membrane Protein Interactions

Yin¹,

Flynn

2016

Annu. Rev. Biomed. Eng.

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The majority of therapeutics target membrane proteins, accessible on the surface of cells, to alter cellular signaling. Cells use membrane proteins to transduce signals into cells, transport ions and molecules, bind the cell to a surface or substrate, and catalyze reactions. Newly devised technologies allow us to drug conventionally “undruggable” regions of membrane proteins, enabling modulation of protein–protein, protein–lipid, and protein–nucleic acid interactions. In this review, we survey the state of the art in high-throughput screening and rational design in drug discovery, and we evaluate the advances in biological understanding and technological capacity that will drive pharmacotherapy forward against unorthodox membrane protein targets.

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“…Pam3CSK4 (InvivoGen, San Diego, CA) was added to the culture medium at a final concentration of 1 mg/mL unless otherwise stated. CU-T12-9 30 (Tocris Bioscience, Bristol, United Kingdom) was used at 1 mM.…”

Section: Primary Human Cd34mentioning

confidence: 99%

Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

Eriksson¹,

Peña-Martínez²,

Ramakrishnan³

et al. 2017

Blood Advances

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Key Points• TLR1 is upregulated on primitive AML cells.• Agonistic targeting of TLR1/TLR2 induces apoptosis and differentiation of primitive AML cells in vivo.Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities.Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary MLL-AF9 AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murine AML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined to MLL-rearranged AML.We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects.

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Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists

Cited by 72 publications

References 56 publications

HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

HMGB1 Activates Proinflammatory Signaling via TLR5 Leading to Allodynia

Drugging Membrane Protein Interactions

Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

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