HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses

Yanai, H. et al. Nature. 462, 99 - 104 (2009)

Speaker: Hsueh-Chi Lu (呂學奇)                                  Time: 13:10~14:00, Apr. 14, 2010

Commentator: Dr. Chun-Keung Yu (余俊強博士)       Place: Room 601

Abstract:

Innate immunity serves the first line to protect host cells from pathogen invasion. Pathogen-associated molecular patterns (PAMPS), such as microbial nucleic acids, can be sensed by pattern recognition receptors (PRRs), such as endosomal toll-like receptors (TLRs) and cytosolic receptors.To gain further insights of these nucleic acids-sensing systems, the authors want to know whether any molecule can help PRRs detect microbial nucleic acids. First, they identified some proteins which could bind B-form DNA,a synthetic DNA, to trigger downstream immune responses. Through the mass spectrometry, they revealed that these proteins were high-mobility group box (HMGB) proteins 1, 2 and 3. HMGB proteins are expressed in the nucleus, cytoplasm and extracellular fluids. In the nucleus, HMGB proteins bind DNA to facilitate some transcription factors. Beside this, HMGB proteins also can activate some TLRs (1) or stimulate pro-inflammatory cytokines productions(2). Surprisingly, they also found that HMGB1 and HMGB3 bound synthetic RNA (polyI:C) and triggered downstream immune responses but HMGB2 only interacted with B-form DNA, not polyI:C. Silencing of HMGB proteins or HMGB^-/- cells showed lower immune responses upon stimulation of synthetic or viral nucleic acids. These data suggest that HMGBs-nucleic acids complex can induce strong immune responses. Finally, they found cytosolic nucleic acid-sensing receptors required HMGB proteins to activate innate immune signalling pathways, including IRF3 and NF-kB. The same requirement of HMGB proteins also was observed in nucleic acid-mediated TLR3, TLR7 and TLR9 pathways. Collectively, HMGB proteins serve as an universal sensor of nucleic acids and trigger subsequent immune response via different PRRs.

References:

1. Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007)

2. Andersson, U. et al. High Mobility Group 1 Protein(HMG-1) Stimulates Proinflammatory Cytokines Synthesis in Human Monocytes. J. Exp. Med. 192, 565-570 (2000)