User:Tbento2015/sandbox

Function

The protein encoded by this gene is a member of the toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity.

The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta, and in myelomonocytic subpopulation of the leukocytes.

It cooperates with LY96 (also referred as MD-2) and CD14 to mediate in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness.

TLR4 signaling responds to signals by forming a complex using an extracellular leucine-rich repeat domain (LRR) and an intracellular toll/interleukin-1 receptor (TIR) domain. LPS stimulation induces a series of interactions with several accessory proteins which form the TLR4 complex on the cell surface. LPS recognition is initiated by an LPS binding to an LBP protein. This LPS-LBP complex transfers the LPS to CD14. CD14 is a glycosylphosphatidylinositol-anchored membrane protein that binds the LPS-LBP complex and facilitates the transfer of LPS to MD-2 protein, which is associated with the extracellular domain of TLR4. LPS binding promotes the dimerization of TLR4/MD-2. The conformational changes of the TLR4 induce the recruitment of intracellular adaptor proteins containing the TIR domain which is necessary to activate the downstream signaling pathway.

Several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.

Most of the reported effects of TLR4 signaling in tumors are pro-carcinogenic mainly due to contributions of proinflammatory cytokine signaling (whose expression is driven by TLR-mediated signals) to tumor-promoting microenvironment.

TLR4 Signaling

Upon LPS recognition, conformational changes in the TLR4 receptors result in recruitment of intracellular TIR-domains containing adaptor molecules. These adaptors are associated with the TLR4 cluster via homophilic interactions between the TIR domains. There are four adaptor proteins involved in two major intracellular signaling pathways.

MyD88 - dependent pathway

The MyD88-dependent pathway is regulated by two adaptor-associated proteins: Myeloid Differentiation Primary Response Gene 88 (MyD88) and TIR Domain-Containing Adaptor Protein (TIRAP). TIRAP-MyD88 regulates early NF-κβ activation and production of proinflammatory cytokines, such as IL-12. MyD88 signaling involves the activation of IL-1R-Associated Kinases (IRAKs) and the adaptor molecules TNF Receptor-Associated Factor 6 (TRAF6). TRAF6 induces the activation of TAK1 (Transforming growth factor-β-Activated Kinase 1) that leads to the activation of MAPK cascades (Mitogen-Activated Protein Kinase) and IKK (IκB Kinase). IKKs' signaling pathway leads to the induction of the transcription factor NF-κβ, while activation of MAPK cascades lead to the activation of another transcription factor AP-1. Both of them have a role in the expression of proinflammatory cytokines.

MyD88 - independent pathway

This TRIF-dependent pathway involves the recruitment of the adaptor proteins TIR-domain-containing adaptor inducing interferon-β (TRIF) and TRIF-related Adaptor Molecule (TRAM). TRAM-TRIF signals activate the transcription factor Interferon Regulatory Factor-3 (IRF3) via TRAF3. IRF3 activation induces the production of type 1 interferons.

SARM: Negative regulator of the TRIF-mediated pathway

A fifth TIR-domain-containing adaptor protein called Sterile α and HEAT (Armadillo motif) (SARM) is a TLR4 signaling pathway inhibitor. SARM activation by LPS-binding inhibits -TRIF-mediated pathways but does not inhibit MyD88-mediated pathways. This mechanism prevents an excessive activation in response to LPS which may lead to inflammation-induced damage such as sepsis.

Peer Review #1

"Function" section: You wrote "TLR4 signaling response is a complex formed". I believe this has a grammatical error: the response is a complex? Or the TLR4 responds to signals by forming a complex?

"Function" section: I am confused by the statement "LPS binds a binding protein (LBP), which transfer to CD14." I think this should be re-worded for clarity (e.g. "Upon interaction with the binding protein LBP, LPS binds to CD14.").

"Function" section: For the "The conformational changes of the TLR4 homodimer..." statement, if TLR4 is binding with MD-2, wouldn't this complex be a "heterodimer" since they are 2 different proteins?

MyD88-dependent section: For the statement of "MAPK cascades, JUN N-terminal kinase (JNK) and p38", are you referring to JNK and p38 as specific MAPK cascade pathways? If so, I believe it can be written as "...MAPK cascades for JUN N-terminal kinase (JNK) and p38."

MyD88-independent section: I do not understand this sentence "Via TRAF3 activate the interferon regulatory factor-3 (IRF3) which induce the production of type 1 interferons." This needs grammatical changes, perhaps a crucial word is missing? Also, make sure the subjects and verbs match singular/plural tense.

SARM: This sentence needs to be fixed "...inhibits -TRIF-mediated pathway, but not MyD88-mediated".

Thank you Peer Review #1 for your suggestions.

Peer Review #2

"Function," I would introduce your topic (TLR4) as opposed to "the protein encoded by this gene"

"Function" "TLR4 signaling responds to signals by forming complex formed by an extracellular leucine-rich repeat domain (LRR) and an intracellular toll/interleukin-1 receptor (TIR) domain" is a little confusing... maybe you could say "The TLR4 receptor responds to signals by forming a complex with LRR and TIR."

"TLR4 signaling"- again, maybe you could introduce the 4 proteins and 2 pathways in the intro paragraph, it makes it easier for the reader to follow.

"General Note" pictures help to understand complex pathways such as these.

Peer Review #3

This article needs some general grammatical fixes, but overall I really like how you organized the information. I know we talked about how difficult it can be to add pictures to these articles, but in this case I think a picture of the pathways would be really beneficial, especially since these pathways a well characterized.