Endogenous HMGB1 regulates autophagy.
Autophagy clears long-lived proteins and dysfunctional organelles and generates substrates for adenosine triphosphate production during periods of starvation and other types of cellular stress. Here we show that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule, is a critical regulator of autophagy. Stimuli that enhance reactive oxygen species promote cytosolic translocation of HMGB1 and thereby enhance autophagic flux. HMGB1 directly interacts with the autophagy protein Beclin1 displacing Bcl-2. Mutation of cysteine 106 (C106), but not the vicinal C23 and C45, of HMGB1 promotes cytosolic localization and sustained autophagy. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin1 and sustaining autophagy. Thus, endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death.
Tang
Daolin
D
Damage Associated Molecular Pattern Molecule Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15219, USA. tangd2@upmc.edu
Kang
Rui
R
Livesey
Kristen M
KM
Cheh
Chun-Wei
CW
Farkas
Adam
A
Loughran
Patricia
P
Hoppe
George
G
Bianchi
Marco E
ME
Tracey
Kevin J
KJ
Zeh
Herbert J
HJ
Lotze
Michael T
MT
D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D024243:HMGB1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference; D013217:Starvation / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; D024243:HMGB1 Protein
Exp Cell Res. 2006 Nov 1;312(18):3526-38
16962095
Proc Natl Acad Sci U S A. 1973 Mar;70(3):750-4
4197626
Mol Cell. 2008 Jun 20;30(6):678-88
18570871
Science. 1999 Jul 9;285(5425):248-51
10398600
J Cell Biol. 1974 Oct;63(1):295-9
4371190
J Cell Biol. 2009 Jan 26;184(2):241-52
19171757
Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):131-40
20123075
Nat Rev Immunol. 2005 Apr;5(4):331-42
15803152
Cell Death Differ. 2010 Apr;17(4):666-76
19834494
Nature. 2010 Mar 4;464(7285):104-7
20203610
Cell. 2008 Jan 11;132(1):27-42
18191218
Oncogene. 2010 Sep 23;29(38):5299-310
20622903
Immunity. 2008 Jul 18;29(1):21-32
18631454
Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
17717517
Cell. 2005 Sep 23;122(6):927-39
16179260
J Immunol. 2007 Jul 15;179(2):1236-44
17617616
J Cell Biol. 2005 Nov 21;171(4):603-14
16286508
Autophagy. 2007 Nov-Dec;3(6):542-5
17611390
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12351-6
12209006
Nat Cell Biol. 2008 Jun;10(6):676-87
18454141
Nature. 2009 Nov 5;462(7269):99-103
19890330
J Immunol. 2007 Aug 15;179(4):2330-8
17675494
FEBS Lett. 2003 Aug 28;550(1-3):107-13
12935895
EMBO J. 2007 Apr 4;26(7):1749-60
17347651
Leukemia. 2010 Jan;24(1):177-86
19890377
Trends Cell Biol. 2007 Sep;17(9):422-7
17804237
Am J Respir Cell Mol Biol. 2009 Dec;41(6):651-60
19265175
Curr Opin Investig Drugs. 2009 Dec;10(12):1269-79
19943199
Annu Rev Immunol. 2010;28:367-88
20192808
Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18030-5
15596714
Nature. 2002 Jul 11;418(6894):191-5
12110890
J Exp Med. 2007 Nov 26;204(12):2913-23
17984303
J Leukoc Biol. 2007 Mar;81(3):741-7
17135572
J Immunol. 2007 Jun 1;178(11):7376-84
17513788