Medical Sciences, Beijing, China Beijing, Sciences, Medical www.landesbioscience.com 1 Jia Baohui Implications neurodegenerative in diseases 14-3-3 formation aggresome and P edu *Correspondence to: Yi Zhou; E-mail: yzhou@fsu. http://dx.doi.org/10.4161/pri.28123 02/18/2014 Online: Published 02/05/2014 Accepted: 01/10/2014 Submitted: neurodegeneration bodies, inclusion chaperones, protein aggregation, misfolding, Keywords: Department of Biomedical Sciences; Florida State University College of Medicine; Tallahassee, FL USA; USA; FL Tallahassee, ofMedicine; College University State Florida Sciences; ofBiomedical Department Rizkallah jcs.126102 86 proteins to aggresomes. misfolded chaperone-associated protein targets to: Xu Graham View Z, Extra rion 8:2,173–177;March/April 2014;©2014LandesBiosciencerion ; PMID:23843611 R, Hurt R, 1,2 14-3-3, aggresomes, protein 14-3-3, aggresomes, , Yuying Wu M, Wang M, ; http://dx.doi.org/10.1242/ J Cell Sci 2013 JCell Sci Y, Wu K, Foote K,

1 and Yi Zhou Yi and 14-3-3 Y, Y. Zhou 14-3-3 M, Liang M, ; 126 : 4173 F, 1,* - P proteins. This leads to the failure of nerve of nerve failure to the leads This proteins. of misfolded clearance and generation the between imbalance achronic often is there diseases, neurodegenerative In chain (DIC) and an Hsp70 co-chaperone Hsp70 an co-chaperone and (DIC) chain 14-3-3 dynein-intermediate the both to of binding adimeric involves complex molecular This aggresomes. to transport motors for dynein to proteins misfolded adaptor chaperone-associated to recruit amolecular as 14-3-3that functions determined study, have we arecent In proteins. huntingtin bymutant induced of aggresomes formation for the pensable indis 14-3-3 be to shown were proteins the Previously, cells. in aggregates tein pro of toxic clearance and sequestration for mechanism defense another as emerged has pathway macroautophagy aggresome- the degradation, proteasomal and refolding chaperone-mediated to addition In diseases. neurodegenerative environmental insults or oxidative stress. stress. or oxidative insults environmental mutations, by genetic caused be can Proteinmisfolding proteins. aggregated and of misfolded accumulation the is diseases neurodegenerative during the process of neurodegeneration. process the during stress protein misfolded managing role in its into insights mechanistic provide may findings our diseases, neurodegenerative various in 14-3-3 implicated As been has 3(BAG3). athanogene Bcl-2-associated A common feature of various of various feature A common underlie the pathogenesis of many of many pathogenesis the underlie aggregation and misfolding rotein Introduction Prion

2 - - Guanganmen Hospital; China Academy of Chinese ofChinese Academy China Hospital; Guanganmen intracellular transport. intracellular of disruption and inhibition proteasome pore formation, including of mechanism, avariety through viability and functions cell impede which proteins, misfolded aggregation-prone excess with to cope cells cells of all kingdoms of life have have of life kingdoms of all cells Therefore, death. to cell lead ultimately and functions, cellular normal perturb that aggregates proneare to forming proteins misfolded nonfunctional, being just do not fold More correctly. than some proteins of biogenesis, byproduct inevitable an As molecules. functional to become conformations dimensional lysosome-dependent macroautophagy. by degraded subsequently and aggresome the to as referred structure a perinuclear into transported actively be can proteins aggregated and misfolded processes, cellular of these capacity the exceeds proteins of misfolded production the When degradation. proteasomal and refolding assisted chaperone molecular includes that system protein quality-control elaborate an evolved have protein, cells in this process. this in role important to playan shown we have 14-3-3 on the which proteins, emphasis special with process formation aggresome of the understanding our in evidence recent discuss will review short This Response to Misfolded Protein to Misfolded Response Aggresome: An Active Cellular Proteins must attain appropriate three- attain must Proteins To of misfolded prevent aggregation Aggregates 1-3 Extr a Vi 173 e 4-6 w

©2014 Landes Bioscience. Do not distribute. 174 (proteostasis). protein homeostasis to maintain systems control quality sophisticated developed aggregated proteins are recruited to the to the recruited are proteins aggregated and whereby misfolded process, cellular active an is of aggresomes formation The proteins. misfolded undegraded of aggregated, composed mainly is and solvents or detergent aqueous in solubility apoor It has cell. of the region perinuclear atthe localized body inclusion cell. the in protein aggregates misfolded rolemanaging in important playan may aggresome, termed structure, cellular a that suggests decades two last the in poorly understood, evidence accumulated is of protein aggregates clearance for the pathway cellular the While aggregates. of formation the in resulting proteins, folded or partially unfolded other with tend to interact proteins misfolded cell, the in accumulated Once cell. of the capacity proteolytic the in or adefect proteolysis, proteasome cytoplasmic to protein inaccessible misfolded the renders mutation that of genetic a result be could This conditions. pathological certain under occur protein does of misfolded However, accumulation the proteostasis. cellular the maintaining in effective are control systems system. ubiquitin-proteasome the through cells from eliminated then are proteins to fold properly, fail however, they Once activities. cellular involved in are proteins folded correctly the only that ensuring thereby processes, trafficking intracellular and cytoplasm both in function pathways chaperone-assistance The conformations. favorable energetically by acquiring refolding help their and proteins damaged with associate also They (ER). reticulum endoplasmic the in proteins of nascent folding the for assisting important are Hsps (Hsps). heat-shock proteins as known also chaperones, molecular by the mediated to be appears defense cellular of line important an understanding, proteins by the proteasome. the by proteins of ubiquitinated degradation the with ends and of enzymes, by a set complex protein (polyubiquitination) misfolded the of modification and recognition the with The aggresomes is a single prominent asingle is aggresomes The protein quality- these general, In

5,8,9 This cellular process begins begins process cellular This 7 Based on our current current on our Based 10 7,11 motifs. phosphoserine specific containing proteins target regulating to and binding by functions their exert and dimers hetero- homo- and/or as exist proteins huntingtin protein. amutant expressing ectopically cells the in inclusions perinuclear aggresome-like with 14-3-3 colocalize that proteins observation by an indicated first was pathway 14-3-3 aggresome the in proteins expanded huntingtin protein (Htt86Q). huntingtin expanded polyglutamine- another of expression the by induced formation aggresome inhibits significantly cells mammalian in RNA) 14-3-3 biological processes. biological of range awide involved in are that proteins over 200 with to interact known been (m MTOC to the on microtubules transported motor retrogradely and dynein-dynactin expressed in the brain. the in expressed abundantly most are that proteins with the lysosome. the with fusion subsequent and autophagosome of the formation the contents through of aggresome degradation targeted the to leads that aprocess macroautophagy, by clearance eventual for their proteins aggregated and misfolded concentrate helps that mechanism acellular is formation aggresome that indicates evidence More recently, emerging aggregates. small and proteins misfolded cytotoxic by sequestering cells protect aggresomes that proposed previously was (Htt103QP). protein huntingtin a disease-related of targeting Bmh1, aggresomal blocks 14-3-3 homologs yeast one of two encodes bmh1 which of gene, the deletion cells, yeast in process: formation aggresome the in indispensable are isoforms 14-3-3 certain that showed studies two ε ( isoforms homologous structurally but distinct genetically of seven consist and to human yeast from conserved In both studies, 14-3-3 was found to 14-3-3 found was studies, both In , icro η 14-3-3 refers to a family of ubiquitous 14-3-3 to afamily refers 14-3-3: Adaptor AMolecular , for Aggresomalfor Targeting ζ t by siRNAs (small interfering interfering (small ζ by siRNAs 19,20 , ubule ubule of Misfolded Proteins Misfolded of σ , and , and To 14-3-3 date, have proteins 23 raiain c organization Likewise, suppression of Likewise, τ ) in mammals. ) in P 14-16 rion 21 The involvement The of

22 17 Subsequently, They are highly highly are They enter). 18 14-3-3 14-3-3 12,13 β , It It γ 24 ,

250 SOD and GFP- as here (such tested substrates the Moreover, protein). Htt mutant some of protein (e.g., the misfolded a particular to binding its beyond likely is role that a process, formation aggresome the in function abroad to have 14-3-3 appears α aGFP-tagged prone including proteins, aggregation- of several ectopic expression by induced of aggresomes formation 14-3-3 the of promoting capable is study, that we found this In process. formation aggresome of the regulation 14-3-3-dependent underlying mechanism molecular the to investigate cells mammalian and yeast both in analyses level. atamolecular pathway formation aggresome the 14-3-3 regulate might how not clear but yet itproteins, was huntingtin mutant the with interact (SOD GFP-250, dismutase superoxide amutant (CFTR- regulator conducting transmembrane fibrosis cystic ofform the the aggresome. the to transport their facilitates thereby and motor, dynein to the proteins aggregated and misfolded chaperone-associated couples that adaptor amolecular as serves degradation of misfolded and aggregated aggregated and of misfolded degradation macroautophagic targeted in complex Hsp70 of the importance the established have studies Previous 3 (BAG3). athanogene Bcl-2-associated co-chaperone Hsp70 to an binding its through proteins misfolded 14-3-3 that recruits discovered proteins. of misfolded ubiquitination on the by 14-3-3 not dependent does targeting aggresome that suggesting ubiquitinated, different proteins. different of two interaction the to bridge adaptor amolecular as function 14-3-3 can dimer the that showing reports published with line in is finding This cells. mammalian and yeast both in formation aggresome for requirement 14-3-3 afunctional is of dimerization that we determined for 14-3-3 Second, required binding. is atDIC region the that define to further analyses truncation utilized and (DIC), chain intermediate 14-3-3 dynein the and between interaction protein-protein novel -synuclein ( -synuclein We have recently performed a series of aseries We performed recently have Our results further revealed that 14-3-3 that revealed further results Our G85R 26,27 ) and Htt103QP. and ) G85R α 25 -Syn-EGFP), a mutant amutant -Syn-EGFP), First, we identified a we identified First, ) are known to be non- to be known ) are 28,29 Furthermore, we we Furthermore, V olume 8 25 Thus, Thus, Δ F508), I ssue 2

©2014 Landes Bioscience. Do not distribute. www.landesbioscience.com autophagy of misfolded proteins. of misfolded autophagy selective and targeting aggresome based rolechaperone- in to playacritical shown postulate that this coupling is mediated by mediated is coupling this that postulate We complex. dynein onto cytoplasmic the protein cargo misfolded the loads and BAG3 Hsp70 to the co-chaperone binding phosphorylation-dependent a via complex Hsp70 the 1). with 14-3-3(Step interacts Hsp70 the as complex such chaperones, by molecular bound and recognized generally are proteins aggregated and misfolded response, stress acellular As stress. or external mutations of genetic conditions under aggregates toxic form Figure in depicted pathway. formation As aggresome for a14-3-3-mediated model working motor.dynein the and proteins misfolded associated chaperone- between 14-3-3 linker akey is that Together, suggest proteins. data these of misfolded targeting for aggresomal 14-3-3 to BAG3 crucial is binding Consistently,that we found proteins. misfolded chaperone-associated as well Hsp70 a with complex as forming thus BAG3, to phosphorylated directly binds 14-3-3 that revealed analyses biochemical proteins. and aggregates to the aggresome. tothe aggregates and proteins misfolded chaperone-associated targeting motor, thereby dynein the BAG3 and tophosphorylated binds simultaneously A14-3-3 dimer ance. Figure 1. Based on these results, we propose a we propose results, on these Based 30-32 Model for 14-3-3’s role in the aggresome-macroautophagy pathway. Numbers denote various steps during aggresome formation and clear and formation aggresome during steps various denote pathway. Numbers aggresome-macroautophagy the 14-3-3’s in for role Model Particularly, BAG3 has been been BAG3 has Particularly,

1 , misfolded proteins proteins , misfolded

5,30 Our Our selective macroautophagy. by proteins of misfolded/aggregated degradation to targeted formation aggresome chaperone-associated the linking evidence provided have reports 5). (Step protein aggregates of cytotoxic clearance and degradation the in result will lysosome and autophagosome the between fusions Finally, 4). (Step membrane of autophagic recruitment the through autophagosome into an turn can Subsequently, aggresome 3). the (Step aggresome the to form MTOC the toward microtubule along transported then is complex cargo The 2). (Step respectively BAG3 or with DICmonomer interacts of 14-3-3, each binding which in a dimeric p62/SQSTM1-dependent manner. p62/SQSTM1-dependent a in by macroautophagy degradation to promote shown BAG3 substrate was previous studies showing the importance importance the showing studies previous with consistent is This of aggresomes. formation the as well 14-3-3 as binding for of BAG3 critical phosphorylation is the that demonstrated we have hand, other On the process. macroautophagy role of 14-3-3 a potential the in investigate to directed be should studies future 14-3-3 BAG3, and between interaction protein-protein identified of our light It is worth noting that several recent recent several that noting It worth is Prion

33,34 Specifically, Specifically, 35 In In during misfolded protein stress. misfolded during activated cascades signaling novel cellular define potentially may studies these as BAG3 phosphorylation, regulate that kinase/phosphatase) (protein factors cellular the identify to further interest pathological conditions. pathological in proteins aggregated and of misfolded accumulation with for coping mechanism acytoprotective pathway, representing formation aggresome to the analogous is that process by acellular mediated likely is bodies of inclusion formation the evidence, by recent suggested As characteristics with the aggresome. the with characteristics morphological and biochemical similar share that bodies inclusion intracellular of presence by the characterized are aggresome formation. aggresome promoting in activation of protein kinase in Alzheimer disease, mutant huntingtin huntingtin mutant disease, Alzheimer in tangles neurofibrillary disease, Parkinson in bodies Lewy as such diseases, of neurodegenerative anumber in bodies acomponent of as inclusion identified been 14-3-3 previously have proteins and Neurodegenerative Diseases and Neurodegenerative Many neurodegenerative diseases diseases neurodegenerative Many 14-3-3, Aggresomes, 36-39 26 It will be of be It will Interestingly, Interestingly, 175 - 40

©2014 Landes Bioscience. Do not distribute. 10 11 9. 7. 8. 6. 5. 4. 2. 176 JW. Kelly A, Dillin RI, Morimoto WE, alch 1 3. lateral sclerosis. lateral Amyotrophic in dismutase superoxide of mutant inclusions aggresome-like and Huntington’s in disease, aggregates sweeper to facilitate the sequestration and and sequestration the to facilitate sweeper a 14-3-3 as that act may who hypothesized Hachiya, and by Kaneko ago years several of 14-3-3 proposed was afunction such Indeed, of neurodegeneration. process the during survival neuronal promoting in factor important an is of proteins family this that we expect assays, cell-based the in to aggresomes proteins misfolded by targeting cells protects 14–-3-3 As aggresomes. and bodies inclusion between similarity the establishes further aggresome the in present 14-3-3 also is .

. .

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