High mobility group box 1 (HMGB1) is a nuclear protein and a late mediator of sepsis, inducing a pro-inflammatory response when secreted. Understanding the extracellular secretion of HMGB1 is important to control inflammation but it is not well understood, in part because HMGB1 does not comprise a signal peptide that targets it to the endoplasmic reticulum. Hyun-Soo Cho, Jeon-Soo Shin and colleagues have previously described how secretion of HMGB1 is regulated by its phosphorylation and, now (p. 29), find that glycosylation also has a role in HMGB1 secretion. The authors use liquid chromatography tandem mass spectrometry and gel-shift analysis to show that HMGB1 is N-glycosylated within the consensus motifs at N37 and N134, and within the non-consensus motif at N135. Non-glycosylated HMGB1 proteins show nuclear localisation, strong binding to DNA, low binding to the nuclear export protein CRM1 and rapid degradation following ubiquitylation. There was little extracellular secretion of non-glycosylated HMGB1, even after other post-translational modifications. The authors, therefore, propose that N-glycosylation of HMGB1 at N37, N134 or N135 determines its nucleocytoplasmic transport, extracellular secretion and protein stability.
- © 2016. Published by The Company of Biologists Ltd