N-linked glycosylation plays a crucial role in the secretion of HMGB1

Journal of Cell Science - Tập 129 Số 1 - Trang 29-38 - 2016
Young Hun Kim1,2, Man Sup Kwak2, Jun Bae Park3, Shin Ae Lee2, Jieun Choi4, Hyun‐Soo Cho3, Jeon‐Soo Shin1,5,2
1Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine 2 , Seoul 120-752 , Korea
2Yonsei University College of Medicine 1 Department of Microbiology , , Seoul 120-752 , Korea
3Yonsei University College of Life Science and Biotechnology 3 Department of Systems Biology , , Seoul 120-749 , Korea
4Seoul National University Boramae Hospital, Seoul National University College of Medicine 4 Department of Pediatrics , , Seoul 156-707 , Korea
5Severance Biomedical Science Institute and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine 5 , Seoul 120-752 , Korea

Tóm tắt

ABSTRACT HMGB1 protein is a delayed mediator of sepsis that is secreted to the extracellular milieu in response to various stimulants, inducing a pro-inflammatory response. HMGB1 is devoid of an endoplasmic reticulum (ER)-targeting signal peptide; hence, the mechanism of extracellular secretion is not completely understood, although HMGB1 is secreted after being subjected to post-translational modifications. Here, we identified the role of N-glycosylation of HMGB1 in extracellular secretion. We found two consensus (N37 and N134) and one non-consensus (N135) residues that were N-glycosylated in HMGB1 by performing liquid chromatography tandem mass spectrometry (LC-MS/MS) and analyzing for N-glycan composition and structure. Inhibition of N-glycosylation with tunicamycin resulted in a molecular shift of HMGB1 as assessed by gel electrophoresis. Non-glycosylated double mutant (N→Q) HMGB1 proteins (HMGB1N37Q/N134Q and HMGB1N37Q/N135Q) showed localization to the nuclei, strong binding to DNA, weak binding to the nuclear export protein CRM1 and rapid degradation by ubiquitylation. These mutant proteins had reduced secretion even after acetylation, phosphorylation, oxidation and exposure to pro-inflammatory stimuli. Taken together, we propose that HMGB1 is N-glycosylated, and that this is important for its DNA interaction and is a prerequisite for its nucleocytoplasmic transport and extracellular secretion.

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Journal of Cell Science

Tập 129 Số 1

29-38

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