LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.

Jennifer Dahan (1, 2) , Yann Nouët (1) , Grégory Jouvion (3) , Florence Levillayer (1) , Minou Adib-Conquy (4) , Anne-Marie Cassard-Doulcier (5) , Ali Tebbi (2) , Fany Blanc (6) , Lauriane Remy (2) , Ju Chen (7) , Stefano Cairo (8) , Catherine Werts (9) , Mustapha Si-Tahar (6) , Thierry Tordjmann (10) , Marie-Annick Buendia (1) , Yu Wei (1, 2)

1 Oncogenèse et Virologie Moléculaire
2 PVHB - Pathogenèse des Virus de l'Hépatite B
3 Histopathologie humaine et Modèles animaux
4 Cytokines et Inflammation
5 Faculté de Médecine Paris Sud
6 Défense innée et inflammation
7 UC San Diego - University of California [San Diego]
8 XenTech
9 BGPB - Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall
10 Signalisation calcique et interactions cellulaires dans le foie

Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor κB (NF-κB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-κB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-κB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-κB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-κB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-κB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-κB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells.

Domaines: Sciences du Vivant [q-bio]; Immunité innée; Maladies infectieuses; Pneumologie et système respiratoire

Jennifer Dahan, Yann Nouët, Grégory Jouvion, Florence Levillayer, Minou Adib-Conquy, et al.. LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.. Molecular and Cellular Biology, 2013, 33 (16), pp.3299-308. ⟨10.1128/MCB.00105-13⟩. ⟨hal-01118323⟩