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Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion

 Young Hun Kim  ;  Man Sup Kwak  ;  Bin Lee  ;  Jae Min Shin  ;  Sowon Aum  ;  In Ho Park  ;  Min Goo Lee  ;  Jeon-Soo Shin 
 AUTOPHAGY, Vol.17(9) : 2345-2362, 2021-10 
Journal Title
Issue Date
GORASP2 ; HMGB1 ; HSP90AA1 ; MVB formation ; autophagy ; unconventional protein secretion
Nuclear protein HMGB1 is secreted in response to various stimuli and functions as a danger-associated molecular pattern. Extracellular HMGB1 induces inflammation, cytokine production, and immune cell recruitment via activation of various receptors. As HMGB1 does not contain an endoplasmic reticulum-targeting signal peptide, HMGB1 is secreted via the endoplasmic reticulum-Golgi independently via an unconventional secretion pathway. However, the mechanism underlying HMGB1 secretion remains largely unknown. Here, we investigated the role of secretory autophagy machinery and vesicular trafficking in HMGB1 secretion. We observed that HSP90AA1 (heat shock protein 90 alpha family class A member 1), a stress-inducible protein, regulates the translocation of HMGB1 from the nucleus to the cytoplasm and its secretion through direct interaction. Additionally, geldanamycin, an HSP90AA1 inhibitor, reduced HMGB1 secretion. GORASP2/GRASP55 (golgi reassembly stacking protein 2), ARF1Q71L (ADP ribosylation factor 1), and SAR1AT39N (secretion associated Ras related GTPase 1A), which promoted unconventional protein secretion, increased HMGB1 secretion. HMGB1 secretion was inhibited by an early autophagy inhibitor and diminished in ATG5-deficient cells even when GORASP2 was overexpressed. In contrast, a late autophagy inhibitor increased HMGB1 secretion under the same conditions. The multivesicular body formation inhibitor GW4869 dramatically decreased HMGB1 secretion under HMGB1 secretion-inducing conditions. Thus, we demonstrated that secretory autophagy and multivesicular body formation mediate HMGB1 secretion.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kwak, Man Sup(곽만섭) ORCID logo https://orcid.org/0000-0002-3989-3016
Park, Inho(박인호) ORCID logo https://orcid.org/0000-0003-2190-5469
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
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