Lymphotoxin β Receptor Signaling

Signaling through the LT-βR pathway is a crucial element in the maintenance of this organized microenvironment. It plays important roles in embryonic development and organization of secondary lymphoid tissues and maintenance of their architecture in adults. It binds to specific ligands, such as: LT-α1β2 ; and homotrimmer LIGHT, a recently identified member of TNF superfamily; and the lymphotoxin LT-β. LT-βR activates multiple signaling pathways including transcriptional factor NF-κB , and cell death.The LT-α1β2-LT-βR system is required for the formation of lymphoid tissue as well as the segregation of T- and B-lymphocytes into distinct compartments in the spleen and the formation of germinal centers, which is accomplished by the expression of adhesion molecules and Chemokines. LT-βR binds to TRAFs and activates NF-κB. After triggering of LT-βR by LT-α1β2, two NF-κB pathways are activated. Both the pathways are dependent on the activation of NIK. NIK in turn activates IKK-α, which triggers the degradation of the p52 precursor, p100, to yield the mature p52, which heterodimmerizes with RelB. The other NF-κB-activating pathway that involves the formation of p50-RelA heterodimmers, involving the α, β and γ subunits of the IKK complex.Nuclear translocation and DNA binding of p50-RelA heterodimmers is accomplished through IκB-α phosphorylation and ubiquitin-dependent degradation. LT-βR signaling triggers the degradation of p100 in a NIK- and IKK-α-dependent manner. As a consequence, IκB-δ is degraded, p52-RelB heterodimmers accumulate in the nucleus and regulate genes that are crucial for the normal development of lymphoid organs; whereas the upregulation of VCAM1 and CXCL1 requires the activation of p50-RelA heterodimmers. In response to the activation of PI3K by the LIGHT-actived LT-βR, Akt is recruited by PIP3 and is phosphorylated by PDK-1 on Thr308 in the kinase domain. Actvated Akt, in turn phosphorylates the IKKs.LIGHT protein causes cell death by apoptosis of various tumor cells expressing LT-βR. Upon the binding of LIGHT to LT-βR, TRAF2 is first recruited to the receptor followed by TRAF3 and cIAP1 , during which the BIR1 domain of cIAP1 is cleaved. cIAP1 inhibits activity of Caspases by direct interaction with Caspases. The initial LIGHT-LT-βR complex also triggers the mitochondria-mediated apoptosis pathway through the activation of TRAF2 and also through the activation of TRAF3, which induces the release of SMAC from mitochondria. The cytosolic SMAC is then recruited to the receptor via its interaction with the BIR3 domain of cIAP1. The N-terminus of SMAC antagonizes the function of cIAP1 while the C-terminus works in concert with N-terminus to promote LT-βR-induced apoptosis.Inflammation-associated lymphoid organogenesis is found in some autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and spontaneous autoimmune diabetes. Biological immunosuppressive strategies that are available at present mainly involve the inhibition of pro-inflammatory mediators, such as TNF or chemokines.