Journal of Cell Science h u ornyGaa,MlyFoe eghnLag adRzalh yaHr,Ynhn Wang, Yanchang Hurt, Myra Rizkallah, Raed Zhou* Liang, Yi Fengshan and Foote, Wu Molly Yuying Graham, Kourtney Xu, Zhe aggresomes to proteins chaperone-associated misfolded targets protein 14-3-3 Article Research n oss fsvnmmainioom ( human Moore, isoforms are to mammalian 1982; yeast seven that from of al., consist conserved proteins et and highly are (Boston ubiquitous proteins brain 14-3-3 of the 1967). family in aggresomes expressed a abundantly 14-3-3, to by proteins regulated 2011). Qian, misfolded and Zhang targeting 2011; al., et for (Gamerdinger critical to co- shown al., its were be and (BAG3) et (Hsp70) 3 Ravikumar athanogene 70 Bcl-2-associated protein 2003; chaperone heat-shock al., recently, More et 2005). (Kawaguchi aggresome the process in histone components formation [e.g. critical adaptors as (HDAC6)] along molecular 6 have and deacetylase studies motor transport previous dynein underlying (MTOC) understood, the the fully identified While for center not 2005). are al., details organizing et adaptors molecular Ravikumar 2010; microtubule al., protein et the (Chin to by microtubules dynein–dynactin complex the onto process loaded active motor are an proteins is misfolded which formation in Aggresome also al., but 2000). et aggregates, Kopito, (Garcia-Mata proteasome-dependent macroautophagy small 2002; by of clearance toxicity into their the When facilitate alleviate sequestered which help aggresomes, be only as proteins 2010). known not can bodies misfolded inclusion proteins juxtanuclear al., toxic large misfolded fails, to et degradation response as identified cellular (Tyedmers been aggresome- important recently has the an clearance and and dependent degradation, refolding (Ross autophagy chaperone-assisted cytotoxicity mediated to to addition ubiquitin-proteasome lead In and 2005). perturb that Poirier, functions aggregates forming cellular to normal prone are proteins Misfolded Introduction in observed molecular bodies a inclusion as to functions words: complexes 14-3-3 Key such that link suggest may results be and to These aggregates show cells. protein we mammalian diseases. misfolded which and to neurodegenerative of 14-3-3, chain yeast various cargos targeting of both dynein-intermediate dimerization aggresomal protein in functional the promote chaperone-associated aggresomes entails to both recruiting cascade of adaptor with molecular formation thereby This interacts the (BAG3), aggresomes. 14-3-3 for pathway 3 to aggresome-targeting proteins. crucial transport athanogene new regulatory their a Bcl-2-associated for conserved report motors co-chaperone we of machinery dynein Hsp70 Here, molecular family understood. an the a poorly process, and misfolded is 14-3-3, formation loading motor (DIC) aggresome of dynein Although the isoforms the in aggregates. with step involves protein cargos important toxic that an of of as association clearance recognized the and been mediates has sequestration that motors for dynein organelle to cytoplasmic cargos key proteins a is aggresome The Summary USA 32306, FL Tallahassee, Medicine, of College ( University correspondence State for Florida *Author Sciences, Biomedical of Department o:10.1242/jcs.126102 doi: 4173–4186 126, ß Science Cell of Journal 2013 June 19 Accepted Rsnus ta. 00 agadSae,19) h crystal The 1996). Shakes, and Wang 2000; al., et (Rosenquist 03 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2013. erpr eeta grsm omto sprofoundly is formation aggresome that here report We grsm,1--,Dni,BG,Adaptor BAG3, Dynein, 14-3-3, Aggresome, [email protected] ) b , e , g , c , t / h , f and s ) nlsosi eti erdgnrtv iess(Hashiguchi their diseases of neurodegenerative certain consequence in a as inclusions such be proteins ( may disease-related with bodies associations inclusion inclusion various these in 2012). mutant assembles Zhou, 14-3-3 and why it (Foote and disease, However, bodies how 2004). disease, al., known al., et not et Umahara Alzheimer’s is 2002; Parkinson’s (Chen al., etc. et disease, Kawamoto in in 2003; Huntington’s in these bodies aggregates tangles with huntingtin Lewy associated bodies neurofibrillary including inclusion disorders, co-localize pathological diseases, proteins neurodegenerative 14-3-3 the that of observation with number the on al., a based have largely et proteins in 14-3-3 Fu and addition, implicated Tzivion In 1994; 1996). 1998; been al., Davis, al., et and Zha et neuronal Skoulakis 2002; 1997; Avruch, Fantl al., to 2000; et of Peng transcription al., 2000; variety et from wide (Datta binding a ranging development in Through participates 1996). processes, 14-3-3 al., biological proteins, et target motifs Muslin their 1993; to phosphoserine/phosphothreonine al., et specific (Furukawa al., contain et (Rittinger that dimer 14-3-3 opposite simultaneous one in for allowing runs ligands 1999). thereby groove two binding monomer, of ligand binding each the for that arranged way directions is a dimer 14-3-3 such 14-3-3 ligand-bound the in that several Xiao demonstrate of 1995; further al., Co-crystallization complexes as et 1995). (Liu exist al., array they anti-parallel et an nine that in comprising organized reveal monomer helices each proteins with heterodimers, 14-3-3 and homo- human of structures a Sn,pri n a,wihaemjrcmoet of components major are which tau, and parkin -Syn), thsbe yohszdta h rsneo 433poen in proteins 14-3-3 of presence the that hypothesized been has It proteins 200 over with interact to known are proteins 14-3-3 a -synuclein 4173 a - Journal of Cell Science ucin nclsexpressing cells in of role functions potential induce the examine (Ostrerova To to bodies 2006). 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M.H., R.R. experiments and the F.L. of M.F., K.G., majority the performed Z.X. constructs. contributions cDNA Author mutant the Facility of Core imaging, some Molecular with generating the help for of her Pye FSU for Cheryl at and Medicine Confocal Dhanarajan of the Rani College of and Didier FSU Ruth the constructs thank in HDAC6 also Facility We the Qiu line. with cell Yi us knockdown Dr providing and and for constructs, Florida) GFP-mDIC the of the (University for for University) (NIH) Sheng (Stanford Zu-hang and Kopito GFP250 R. of the Ron GFPCFTR (University us Dr Zhang providing constructs, Jianhua for cDNA and Birmingham) Sztul at S. 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