TNF / TNFR superfamily

from Wikipedia, the free encyclopedia

The TNF / TNFR superfamily (written out tumor necrosis factor / tumor necrosis factor receptor superfamily ) is a system of currently more than 40 identified ligand and receptor proteins, which are mostly formed by cells of the immune system and which promote cell proliferation , cell survival and cell differentiation , and affect the apoptosis of the responding cells: For this purpose, membrane-bound and / or soluble ligands of the TNF superfamily interact with one or mostly several specific membrane-bound and / or soluble receptors that form the corresponding TNF receptor superfamily. The function of this complex system of ligands and receptors can be seen in particular in the regulation of immunological processes.

TNF superfamily ligands

The TNF superfamily ligands mostly arise as type 2 transmembrane proteins , i.e. proteins whose N-terminus is extracellular. Three monomers of a corresponding ligand combine non- covalently to form a biologically active trimer . The extracellular protein surfaces of the various ligands are only slightly similar to one another, which explains their receptor specificity. Some of the membrane-bound ligands are released in a soluble form through proteolytic cleavage, usually by metalloproteinases (induced by various stimuli). However, some TNF superfamily ligands are also formed as soluble proteins and form secondary membrane-anchored heterotrimeric complexes.

TNF superfamily receptors

The TNF-like receptors are transmembrane proteins of type 1, that transmembrane proteins whose C-terminus is located intracellular. As a typical feature, the receptors of the TNFR superfamily have one to six extracellular cysteine- rich domains. Like the ligands of the TNF / TNFR superfamily, the receptors also form trimers . Some of the receptors, such as B. the TNF receptor type 1 (TNFR1), the TNF receptor type 2 (TNFR2) or the CD40 trimerize before their ligands bind, which depends on the so-called preligand assembly domain (PLAD) located at the N-terminus of the respective receptor . After receptor activation, various cytoplasmic adapter molecules can bind to the intracellular domain of the respective receptor. This in turn enables different intracellular signal cascades to be set in motion, at the end of which a corresponding cellular reaction takes place. Depending on different regulatory mechanisms, it is also possible that a receptor (such as TNFR1) can initiate different signal cascades and thus cause different (even opposing) cellular reactions. Soluble forms can be split off from some of the receptors (through various stimuli), which can then neutralize the associated ligands. According to the intracellular sequences of the receptors, the TNF receptor superfamily can be divided into three groups:

  1. The first group includes receptors with so-called death domain ( death domains ) in its intracellular part. After activation of these receptors, various intracellular adapter molecules, which themselves have a death domain, can attach to the intracellular receptor death domain. One possibility of the resulting signal transduction is the activation of a cascade of different caspases , which ultimately leads to apoptosis (programmed cell death) of the cell. Prominent and well-studied representatives of this first group are the CD95 (Fas) and the TNF type 1 receptor.
  2. Receptors of the second group are characterized by TNF receptor-associated factor (TRAF) -interacting motifs (TIMs) in their cytoplasmic domain. Their activation leads to the accumulation of so-called TNF receptor-associated factors ( TRAF ) on this cytoplasmic TIM domain. This in turn allows different signal transduction pathways to be initiated, such as B. the NF-κB path, JNK or p38 . Representatives of this group of receptors include TNFR2 , the lymphotoxin-β receptor (LTβR) and herpes virus entry mediator (HVEM).
  3. Receptors of the third group do not transmit signals because they have no functional intracellular domains. However, these receptors compete with the signal-transducing receptors for the ligands and thus regulate their activity. This third group includes e.g. B. decoy receptor 1 (DcR1), decoy receptor 3 (DcR3) or osteoprotegerin (OPG).

credentials

  1. a b c d e f g T. Hehlgans, K. Pfeffer (2005): The intriguing biology of the tumor necrosis factor / tumor necrosis factor receptor superfamily: players, rules and the games. In: Immunology Vol. 115, pp. 1-20. PMID 15819693 doi : 10.1111 / j.1365-2567.2005.02143.x
  2. Locksley, RM, Killeen, N., Leonardo, MJ (2001). The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104 (4), 497-501. PMID 11239407
  3. ^ Mingyi Sun, Pamela J. Fink: A New Class of Reverse Signaling Costimulators Belongs to the TNF Family . In: The Journal of Immunology . tape 179 , no. 7 , October 1, 2007, ISSN  0022-1767 , p. 4307-4312 , doi : 10.4049 / jimmunol.179.7.4307 , PMID 17878324 ( jimmunol.org [accessed January 30, 2018]).
  4. MacEwan, DJ (2002): TNF ligands and receptors - a matter of life and death. British Journal of Pharmacology 135, 855-875. PMID 11861313
  5. Chan, FK, Chun, HJ, Zheng, L., Siegel, RM, Bui, KL, and Lenardo, MJ (2000). A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351-2354. PMID 10875917
  6. Nagata, S. (1997). Apoptosis by death factor. Cell 88, 355-365. PMID 9039262
  7. Dempsey, PW, Doyle, SE, He, JQ, Cheng, G (2003). The signaling adapters and pathways activated by TNF superfamily. Cytokine Growth Factor Rev. 14, 193-209. PMID 12787559

Web links