The role of the co-chaperone BAG3 in selective macroautophagy: implications for aging and disease

  • Christian Behl
Part of the Research and Perspectives in Alzheimer's Disease book series (ALZHEIMER)


Maintenance of protein homeostasis, correct protein folding, refolding and clearance is of central importance for the function and survival of every cell. Here, the degradation of proteins is of particular importance, especially during aging and certain degenerative disorders when the protein load is increased. During cellular aging as well as under acute stress, there is a reciprocal change in expression of two members of the BAG (Bcl-2-associated athanogene) family, BAG1 and BAG3. While BAG1 serves an important function during the degradation of ubiquitinated proteins via the proteasome, BAG3 is the mediator of a novel macroautophagy pathway. This BAG3-mediated macroautophagy is based on the specificity of heat shock protein (HSP) 70 for misfolded proteins and also involves other protein partners, such as HSPB8, sequestosome-1/p62 (SQSTM1/p62) and the autophagosome protein LC3. BAG3 directly mediates the targeting and transport of degradation-prone substrates into aggresomes via the microtubule-motor dynein and also works independently of substrate ubiquitination.


Amyotrophic Lateral Sclerosis Misfolded Protein Autophagy Pathway Cytosolic Component BAG3 Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Arias E, Cuervo AM (2011) Chaperone-mediated autophagy in protein quality control. Curr Opin Cell Biol 23:184–189PubMedCrossRefGoogle Scholar
  2. Behl C (2011) BAG3 and friends: co-chaperones in selective autophagy during aging and disease. Autophagy 7:795–798Google Scholar
  3. Carra S, Seguin SJ, Landry J (2008a) HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy. Autophagy 4:237–239PubMedGoogle Scholar
  4. Carra S, Seguin SJ, Lambert H, Landry J (2008b) HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. J Biol Chem 283:1437–1444PubMedCrossRefGoogle Scholar
  5. Chang HC, Tang YC, Hayer-Hartl M, Hartl FU (2007) SnapShot: molecular chaperones, Part I. Cell 128:212PubMedCrossRefGoogle Scholar
  6. Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S, Bendotti C, De Biasi S, Poletti A (2010) The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet 19:3440–3456PubMedCrossRefGoogle Scholar
  7. Dice JF (2007) Chaperone-mediated autophagy. Autophagy 3:295–299PubMedGoogle Scholar
  8. Dillin A, Cohen E (2011) Ageing and protein aggregation-mediated disorders: from invertebrates to mammals. Philos Trans R Soc Lond B Biol Sci 366:94–98PubMedCrossRefGoogle Scholar
  9. Fleming A, Noda T, Yoshimori T, Rubinsztein DC (2011) Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol 7:9–17PubMedCrossRefGoogle Scholar
  10. Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C (2009) Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. EMBO J 28:889–901PubMedCrossRefGoogle Scholar
  11. Gamerdinger M, Kaya AM, Wolfrum U, Clement AM, Behl C (2011) BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Rep 12:149–156PubMedCrossRefGoogle Scholar
  12. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858PubMedCrossRefGoogle Scholar
  13. Johansen T, Lamark T (2011) Selective autophagy mediated by autophagic adapter proteins. Autophagy 7:279–296PubMedCrossRefGoogle Scholar
  14. Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898PubMedCrossRefGoogle Scholar
  15. Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11:579–592PubMedCrossRefGoogle Scholar
  16. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115:727–738PubMedCrossRefGoogle Scholar
  17. Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530PubMedCrossRefGoogle Scholar
  18. Lanneau D, Wettstein G, Bonniaud P, Garrido C (2010) Heat shock proteins: cell protection through protein triage. Scientific World Journal 10:1543–1552PubMedCrossRefGoogle Scholar
  19. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42PubMedCrossRefGoogle Scholar
  20. Li G, Jiang H, Chang M, Xie H, Hu L (2011) HDAC6 alpha-tubulin deacetylase: a potential therapeutic target in neurodegenerative diseases. J Neurol Sci 304:1–8PubMedCrossRefGoogle Scholar
  21. McCollum AK, Casagrande G, Kohn EC (2010) Caught in the middle: the role of Bag3 in disease. Biochem J 425:e1–e3CrossRefGoogle Scholar
  22. Mizushima N (2007) Collaboration of proteolytic systems. Autophagy 3:179–180PubMedGoogle Scholar
  23. Nandi D, Tahiliani P, Kumar A, Chandu D (2006) The ubiquitin-proteasome system. J Biosci 31:137–155PubMedCrossRefGoogle Scholar
  24. Rautou PE, Mansouri A, Lebrec D, Durand F, Valla D, Moreau R (2010) Autophagy in liver diseases. J Hepatol 53:1123–1134PubMedCrossRefGoogle Scholar
  25. Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O'Kane CJ, Brown SD, Rubinsztein DC (2005) Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat Genet 37:771–776PubMedCrossRefGoogle Scholar
  26. Rose C, Menzies FM, Renna M, Acevedo-Arozena A, Corrochano S, Sadiq O, Brown SD, Rubinsztein DC (2010) Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Genet 19:2144–2153PubMedCrossRefGoogle Scholar
  27. Sondermann H, Scheufler C, Schneider C, Hohfeld J, Hartl FU, Moarefi I (2001) Structure of a Bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors. Science 291:1553–1557PubMedCrossRefGoogle Scholar
  28. Stadtman ER (2006) Protein oxidation and aging. Free Radic Res 40:1250–1258PubMedCrossRefGoogle Scholar
  29. Takayama S, Reed JC (2001) Molecular chaperone targeting and regulation by BAG family proteins. Nat Cell Biol 3:E237–E241PubMedCrossRefGoogle Scholar
  30. Tang YC, Chang HC, Hayer-Hartl M, Hartl FU (2007) SnapShot: molecular chaperones, Part II. Cell 128:412PubMedCrossRefGoogle Scholar
  31. Webb JL, Ravikumar B, Rubinsztein DC (2004) Microtubule disruption inhibits autophagosome-lysosome fusion: implications for studying the roles of aggresomes in polyglutamine diseases. Int J Biochem Cell Biol 36:2541–2550PubMedCrossRefGoogle Scholar
  32. Witan H, Kern A, Koziollek-Drechsler I, Wade R, Behl C, Clement AM (2008) Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-superoxide dismutase induces toxicity independent of protein aggregation. Hum Mol Genet 17:1373–1385PubMedCrossRefGoogle Scholar
  33. Witan H, Gorlovoy P, Kaya AM, Koziollek-Drechsler I, Neumann H, Behl C, Clement AM (2009) Wild-type Cu/Zn superoxide dismutase (SOD1) does not facilitate, but impedes the formation of protein aggregates of amyotrophic lateral sclerosis causing mutant SOD1. Neurobiol Dis 36:331–342PubMedCrossRefGoogle Scholar
  34. Yao TP (2010) The role of ubiquitin in autophagy-dependent protein aggregate processing. Genes Cancer 1:779–786PubMedCrossRefGoogle Scholar
  35. Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12:9–14PubMedCrossRefGoogle Scholar
  36. Young JC (2010) Mechanisms of the Hsp70 chaperone system. Biochem Cell Biol 88:291–300PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Institute for PathobiochemistryUniversity Medical Center, Johannes Gutenberg UniversityMainzGermany

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