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Figures
- Fig. 1.
Model of actions and interactions of the HSP network required for normal protein folding and refolding upon acute stress or during chronic stress. HSP families constitute a large group of chaperones that interact with non-native proteins, assisting their correct protein folding. HSPs are constitutively expressed, but their expression levels can increase under conditions of stress. They are mainly divided into groups: sHsp/HSPBs, Hsp70/HSPAs, Hsp90/HSPCs and members of the chaperonin (CCT-Hsp60) family (see main text for details). (A) During de novo protein folding and for the refolding of acute-stress-denatured unfolded proteins, the functional cooperation of different HSPs is primarily aimed at the structural stabilization of native proteins for (re)folding. However, in case of failure of protein folding, HSPs can also assist client degradation through the ubiquitin-proteasome system (UPS) or the autophagy-lysosome pathway. The central component of the chaperone network and folding catalysts is the Hsp70/HSPA family. Hsp40/DNAJs hydrolyze ATP (bound to Hsp70/HSPA) to ADP, increasing the affinity of its substrate-binding domain for unfolded proteins. Nucleotide-exchange factor (NEF) proteins remove ADP and substitute ATP, reducing Hsp70/HSPA’s substrate-binding affinity, allowing release of the folded protein. Proteins that are unable to utilize Hsp70/HSPAs for complete folding are transferred to the chaperonin or the Hsp90/HSPC system. For transfer of substrates from Hsp70/HSPA to Hsp90/HSPC, HOP is required as a co-chaperone. Under acute stress conditions, HSPB oligomers dissociate into dimers to bind unfolded substrates, thereby avoiding irreversible aggregation of client proteins. This process allows ATP-dependent chaperones to assist in the substrates refolding when normal physiological conditions are restored. (B) In the presence of chronic stress, which triggers protein misfolding, re-folding attempts might be particularly unsuccessful. Under such conditions, the HSP network can assist in protein unfolding and disaggregation, and specific targeting of the misfolded or even aggregated proteins for degradation is usually required. Members of each HSP family are shown to interact with misfolded proteins and to reverse the formation of aggregates. However, whether different HSPs functionally cooperate with each other in order to modulate mutated protein toxicity is not yet clear. Solid lines indicate confirmed actions and interactions; hashed lines refer to those that are suggested but not fully proven.
- Fig. 2.
HSP barcodes associate with diverse proteinopathies. Summary of literature pertaining to the effects on proteinopathies of activating either the cytosolic heat shock response (HSR/HSF-1), using HSF-1 activators or HSP90 inhibitors, or overexpressing specific HSPs from the different families (HSPC, HSPA, HSPD/CCT, DNAJ or HSPB). For each disease, evidence was categorized into four levels according to the system or organism in which the effect was examined: in vitro (A), cell studies (B), non-mammalian model systems (C) and mammals (D). Evidence was further graded according to the specific effects of the HSP(s) on the disease: prevention of aggregate formation (black), buffering of toxic effects caused by diseased protein (gray) and absence of effects (white). See main text for further explanation. Numbers in the table correspond to references in the legend. Solid data was cited from review articles, which are displayed as numbers in the gray column below each disease section. Data from orginial articles (higher model organisms, subheadings C and D) are cited in the corrseponding individual cells. reviews, articles with general information used for the figure; polyQ, polyglutamine diseases; Htt, huntingtin; SCA, spinocerebellar ataxia; AR, androgen receptor; PD, Parkinson’s disease; α-syn, α-synuclein; ALS, amyotrophic lateral sclerosis; AD, Alzheimer’s disease; Aβ, amyloid-β; 990, HSP990; AMCL, arimoclomol; GA, geldanamycin; CLST, celastrol; GGA, geranylgeranylacetone; RA, radicicol; A4, drug name (novobiocin analog); PU, PU-H71. References: (1) Jiang et al., 2012; (2) Gunawardena et al., 2003; (3) Bauer et al., 2010; (4) Yousuf et al., 2010; (5) McLear et al., 2003; (6) Hansson et al., 2003; (7) Hay et al., 2004; (8) Tam et al., 2006; (9) Sontag et al., 2013; (10) Tam et al., 2009; (11) Behrends et al., 2006; (12) Kakkar et al., 2013; (13) Abisambra et al., 2012; (14) Hageman et al., 2011; (15) Labbadia et al., 2012; (16) Hageman et al., 2010; (17) our unpublished results; (18) Peterson and Blagg, 2009; (19) Jana et al., 2000; (20) Wacker et al., 2004; (21) Perrin et al., 2007; (22) Zourlidou et al., 2007; (23) Carra and Landry, 2006; (24) Mymrikov et al., 2011; (25) Boncoraglio et al., 2012; (26) Vos et al., 2010; (27) Tue et al., 2012; (28) Fujimoto et al., 2005; (29) Pierce et al., 2010; (30) Labbadia et al., 2011; (31) Neef et al., 2010; (32) Neef et al., 2011; (33) Agrawal et al., 2005; (34) Sittler et al., 2001; (35) Fujikake et al., 2008; (36) Herbst and Wanker, 2007; (37) Cummings et al., 2001; (38) Chai et al., 1999; (39) Carra et al., 2010; (40) Rimoldi et al., 2001; (41) Chan et al., 2000; (42) Adachi et al., 2003; (43) Fliss et al., 1999; (44) Stenoien et al., 1999; (45) Howarth et al., 2007; (46) Stope et al., 2012; (47) Kondo et al., 2013; (48) Thomas et al., 2006; (49) Waza et al., 2005; (50) Waza et al., 2006; (51) Almeida et al., 2011; (52) Rusimini et al., 2011; (53) Katsuno et al., 2005; (54) Malik et al., 2013; (55) Aridon et al., 2011; (56) Gorbatyuk et al., 2012; (57) Redeker et al., 2012; (58) Danzer et al., 2011; (59) Auluck et al., 2002; (60) Auluck et al., 2005; (61) Klucken et al., 2004; (62) Shimshek et al., 2010; (63) Pemberton et al., 2011; (64) Bruinsma et al., 2011; (65) Outeiro et al., 2006; (66) Liangliang et al., 2010; (67) Auluck and Bonini, 2002; (68) Riedel et al., 2010; (69) Song et al., 2013; (70) Gifondorwa et al., 2007; (71) Gifondorwa et al., 2012; (72) Boillée et al., 2006; (73) Koyama et al., 2006; (74) Patel et al., 2006; (75) Blumen et al., 2012; (76) Sharp et al., 2008; (77) Krishnan et al., 2008; (78) Yerbury et al., 2013; (79) Batulan et al., 2006; (80) Kiaei et al., 2005; (81) Kalmar et al., 2008; (82) Kieran et al., 2004; (83) Estes et al., 2011; (84) Gregory et al., 2012; (85) Jinwal et al., 2012; (86) Evans et al., 2006; (87) Tiffany-Castiglioni and Qian, 2012; (88) Hoshino et al., 2011; (89) Veereshwarayya et al., 2006; (90) Carnini et al., 2012; (91) Toth et al., 2013; (92) Wilhelmus et al., 2006; (93) Wilhelmus et al., 2007; (94) Jiang et al., 2013; (95) Pierce et al., 2013; (96) Paris et al., 2010; (97) van der Putten and Lotz, 2013; (98) Dou et al., 2003; (99) Miyata et al., 2011; (100) Abisambra et al., 2010; (101) Opattova et al., 2013; (102) Petrucelli et al., 2004; (103) Dickey et al., 2006; (104) Sinadinos et al., 2013; (105) Chan et al., 2002; (106) Ansar et al., 2007; (107) Wang et al., 2008.
- Fig. 3.
Overview of chaperonopathies caused by mutations in HSPs. Mutations that lead to either recessive (white boxes) or dominant (black boxes) chaperonopathies have been described for six ‘families’ of HSP. Each chaperonopathy is categorized as a neuropathy, myopathy or retina-related disease (cataracts). The mutations in HSPs involved in both recessive and dominant diseases have been shaded gray. h-SP, hereditary-spastic paraplegia; dHMN, distal hereditary motor neuropathy; MN, motor neuropathy; CMT2, Charcot-Marie-Tooth disease 2; DCM, dilated cardiomyopathy; MFM, myofibrillar myopathy; LD, leukodystrophy; MD, muscular dystrophy; CC, congenital cataract; DT, dystrophy.
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