8.A.177. The Tumor Necrosis Factor Ligand Member 6 (TNFL6) Family The TNFL6/FAS protein (CD95L) activates the NHE1 Na⁺/H⁺ exchanger, NHE1 (TC# 2.A.36, a plasma membrane protein that is ubiquitously present in all human cells) (Monet et al. 2016). It functions to regulate intracellular pH removing an intracellular proton in exchange for one extracellular sodium and is involved in heart disease and in promoting metastasis in cancer (Fliegel 2021). Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na⁺/H⁺ exchanger, NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration, and disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Thus, NHE1 is a molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways (Monet et al. 2016).
References:
Fliegel, L. (2021). Role of Genetic Mutations of the Na/H Exchanger Isoform 1, in Human Disease and Protein Targeting and Activity. Mol. Cell Biochem 476: 1221-1232.
Madaio, M.P., I. Czikora, N. Kvirkvelia, M. McMenamin, Q. Yue, T. Liu, H.A. Toque, S. Sridhar, K. Covington, R. Alaisami, P.M. O''Connor, R.W. Caldwell, J.K. Chen, M. Clauss, M.W. Brands, D.C. Eaton, M.J. Romero, and R. Lucas. (2019). The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis. Kidney Int 95: 1359-1372.
Martin-Malpartida, P., S. Arrastia-Casado, J. Farrera-Sinfreu, R. Lucas, H. Fischer, B. Fischer, D.C. Eaton, S. Tzotzos, and M.J. Macias. (2022). Conformational ensemble of the TNF-derived peptide solnatide in solution. Comput Struct Biotechnol J 20: 2082-2090.
Monet, M., M. Poët, S. Tauzin, A. Fouqué, A. Cophignon, D. Lagadic-Gossmann, P. Vacher, P. Legembre, and L. Counillon. (2016). The cleaved FAS ligand activates the Na⁺/H⁺ exchanger NHE1 through Akt/ROCK1 to stimulate cell motility. Sci Rep 6: 28008.
Examples:
TC#	Name	Organismal Type	Example
8.A.177.1.1	*The tumor necrosis factor ligand superfamily member 6, TNFRSF6/FAS or CD95L that activates NHE1 (TC#2.A.36.1.13) (see famiy description) (Monet et al.* 2016).**		CD95L of Homo sapiens

8.A.177.1.2	Tumor necrosis factor ligand superfamily member 14-like protein of 229 aas and 1 TMS.		*TNFR14 of Acipenser ruthenus* (sterlet)**

8.A.177.1.3	Lymphotoxin-alpha isoform X2of 183 aas and possibly 1 TMS.		*Lymphotoxin of Pteropus alecto* (black flying fox)**

8.A.177.1.4	Tumor necrosis factor ligand superfamily member 15, TNFL15 of 251 aas and 1 TMS.		TNFL15 of Chlorocebus sabaeus (Cercopithecus sabaeus)

8.A.177.1.5	CD40 ligand of 237 aas and one N-terminal TMS.		*CD ligand of Fundulus heteroclitus* (mummichog or atlantic killifish)**

8.A.177.1.6	Uncharacterized protein of 296 aas and 1 N-terminal TMS.		*UP of Menidia menidia* (Atlantic silverside)**

8.A.177.1.7	Tumor necrosis factor ligand superfamily member 11 of 274 aas and 1 TMS.		*TNF11 of Colossoma macropomum* (tambaqui; black-finned pacu)**

8.A.177.1.8	Tumer necrosis factor, TNF, of 233 aas with a very hydrophobic TMS near the N-terminus of the protein. A cyclic peptide, solnatide, of 17 aas, modified from TNF (CGQRETPEGAEAKPWYC), residues 177 - 195) activates ENaC (TC# 1.A.6.1.1) (Madaio et al. 2019; Martin-Malpartida et al. 2022).		TNF of Homo sapiens