Chaperones in hepatitis C virus infection

Table 1 Chaperones and their roles in the hepatitis C virus viral life cycle

Chaperone	Subcellular localization	Function in HCV infection/stage of viral life cycle
HSP70 family
GRP75 (HSPA9)	Mitochondrial	Varied expression/activity[66,72]
		Interacts with NS5A[105]
GRP78 (HSPA5)	ER	Regulation of viral protein homeostasis and maintaining a balance between viral and cellular translation to prevent viral protein overload (involves induction of ER stress and the UPR)[43,85-96]
		Increased expression and activity[72,85,88,93,95]
		Associated with the viral genome[70,76]
HSC70 (HSPA8)	Cytosolic	Infectious virion assembly[18,74]
		Potentially contributes to stability of virion structure and viral entry through clathrin-mediated endocytosis[35,74]
		Associated with the viral genome[70,76]
		Increased expression and activity[72,73]
		Knockdown decreases lipid droplet size and virion assembly[18,74]
HSP70 (HSPA1A)	Cytosolic	IRES-mediated translation of viral genome[17,63,64,68,69]
		Increased expression[65-67]
		Knockdown decreases IRES activity and virus production[61,63]
HSP70B’ (HSPA6)	Cytosolic	Associated with 3’ NCR of HCV genome[70]
HSP40 family
DNAJA1	Cytosolic	Co-immunoprecipitates with NS3-NS4A[105]
DNAJA2	Cytosolic	IRES-mediated translation of viral genome[63]
DNAJA3	Mitochondrial	Potentially HCV-induced mitochondrial dysfunction[61,127]
DNAJB1	Cytosolic	Potentially regulates apoptosis[61,117]
		Knockdown decreases virus production[61]
DNAJB6	Cytosolic	Potentially viral RNA replication[105]
		Interacts with NS5B[105]
		Potentially overexpressed[108]
		knockdown decreases viral RNA replication[105]
DNAJB9	ER	Potentially regulates apoptosis[124]
		Varied expression[108]
DNAJC1	ER	Interacts with E1 and E2[107]
DNAJC7	Cytosolic	Potentially regulates apoptosis[118]
		Co-immunoprecipitates with NS3-NS4A[105]
DNAJC8	Cytosolic	Upregulated[119]
DNAJC10	ER	ER protein homeostasis likely benefiting virus production[126]
		Proper folding of LDLR (viral entry)[126]
		Likely overexpressed[125]
DNAJC14	ER	Viral RNA replication[62,121,122]
HSP110 family
HSP105 (HSPH1)	Cytosolic	Overexpressed[129]
HSP70RY (HSPA4)	Cytosolic	Overexpressed[66,130]
		Knockdown decreases viral RNA replication[130]
Hip (HSPBP1)	Cytosolic	Knockdown decreases virus production[62,134]
HSP90 family
GRP94 (HSP90B1)	ER	Regulation of viral protein homeostasis and maintaining a balance between viral and cellular translation to prevent viral protein overload (involves induction of ER stress and the UPR)[95,97,101]
		Suppression of HCV-induced apoptosis[50]
		Potentially HCV-induced liver fibrosis and autoimmune disease[155]
		Overexpressed[95,101,130]
		Knockdown decreases viral RNA replication[130]
HSP90 (HSP90AA1/HSP90AB1)	Cytosolic	HCV RNA replication[138,139,148,149]
		Maturation and stability of HCV proteins[140-143]
		IRES-mediated translation of viral genome[144]
		Circumventing IFNβ response in peripheral B cells[151]
		Potentially regulates miRNA levels in conjunction with GW182[145]
		Interacts with NS5A and NS5B[105,107,143]
		Overexpressed[130,152]
		Knockdown decreases RNA replication[138]
HSP60 family (chaperonins)
HSP60 (HSPD1/HSPE1)	Mitochondrial	Regulates ROS production and apoptosis[159]
		Interacts with core, NS3-NS4A, and viral genome[76,105,107,159]
		Varied expression[66,130]
TRiC/CCT (TCP1/CCT2-8)	Cytosolic	Viral RNA replication by assisting in RC assembly[73]
		Increased activity[129,130]
		Increased TCP1, CCT2, and CCT5 expression[130]
		Decreased CCT4 expression[129]
		CCT4 co-immunoprecipitates with NS3-NS4A[105]
		Knockdown of CCT5 decreases viral RNA replication[73]
Small HSPs
HSP22 (HSPB8)	Cytosolic	Potentially blocks apoptosis[166]
		Overexpressed[119]
HSP27 (HSPB1)	Cytosolic	Potentially decreases apoptosis[164]
		Binds NS5A[164]
		Overexpressed[66]
Other chaperones
ApoJ (clusterin) (CLU)	Cytosolic	Binds to and stabilizes core and NS5A[190]
		Overexpressed[190]
BAG3 (BAG3)	Cytosolic	Co-chaperone of HSP90 family
		Likely blocks ER-stress-induced apoptosis[104]
Calnexin (CANX)	ER	E1/E2 folding and glycosylation[98,107,219,220,223-225]
		HCV-induced ER stress and viral protein homeostasis[98]
		Knockdown decreases virus production[62]
Calreticulin (CALR)	ER	E1/E2 glycosylation[98,107]
		HCV-induced ER stress and viral protein homeostasis[98,101]
		Overexpressed[101,130,226]
		Knockdown decreases virus production[62]
Cyp40 (PPID)	Cytosolic	Lipid trafficking and virion secretion[303]
CypA (PPIA)	Cytosolic	RC formation and viral RNA replication[263,270]
		NS5A and NS5B activation[276,280]
		Viral polyprotein cleavage[283,301]
		Regulates IFN response[304]
		Lipid trafficking and virion assembly and secretion[291,303]
CypB (PPIB)	Cytosolic	RC formation and viral RNA replication[271,272]
		NS5A and NS5B activation[271,272,274,276]
CypD (PPIF)	Mitochondrial	Inhibits mitochondrial function leading to ROS production[308]
EDEM1 (EDEM1)	ER	Downregulated[103,231]
		Binds E1 and E2[230]
		HCV-induced ER stress[230]
		Targets misfolded glycoproteins to ERAD (viral protein homeostasis)[227,228]
EDEM3 (EDEM3)	ER	Binds E1 and E2[230]
		HCV-induced ER stress[230]
		Targets misfolded glycoproteins to ERAD (viral protein homeostasis)[227,228]
Erp72 (PDIA4)	Cytosolic	Increased activity[72]
FKBP38 (FKBP8)	Cytosolic	Co-chaperone of HSP90 family[137]
		HCV RNA replication[137]
		Blocks apoptosis[177]
		Potentially regulates Ca2+ homeostasis by interacting with S100 proteins[175]
		Interacts with NS5A[105,169]
		Knockdown decreases HCV RNA replication[137]
FKBP54 (FKBP5)	Cytosolic	Interacts with NS5B[105]
GRP58 (PDIA3)	Cytosolic	Overexpressed[125,130]
		Knockdown decreases viral RNA replication[130]
MTTP (MTTP)	Cytosolic	Part of the PDI/MTTP heterodimer involved in VLDL biogenesis[193]
		Potentially causes HCV-induced liver steatosis[193,198]
		Viral maturation and secretion[210,211]
		Decreased expression and activity[193,198-200]
p23 (PTGES3)	Cytosolic	Co-chaperone of HSP90 family[179]
		Potentially regulates telomerase activity[180,181]
PDI (P4HB)	ER	Folding and transfer of MTTP to ER as a PDI/MTTP heterodimer involved in VLDL biogenesis[193]
		Increased activity[129]
PDIR (PDIA5)	Cytosolic	Increased activity[72]
Prefoldin	Cytosolic	Co-chaperone of TRiC/CCT[182]
(PFDN1-2/VBP1/PFDN4-6)		Binds F protein[183]
		Regulates cytoskeleton likely to balance virus production in hepatocytes[183]
Prohibitin (PHB/PHB2)	Mitochondrial	Inhibits mitochondrial respiratory function leading to ROS production[237-240]
		Binds core[238]
		Overexpressed[236,237]
SigR1 (SIGMAR1)	Cytosolic	Viral RNA replication immediately after entry[44,234]
		Interorganellar communication between ER and mitochondria[44]
HCV chaperones
Core		Viral RNA stabilization, dimerization, and structural rearrangement[311-315]
		Folding of E1[316]
E1		Proper folding of E2[224,318-320]
E2		Proper folding of E1[317]
NS3		Interconversion of viral RNA species[322]
NS4A		Directs NS3 to ER[323]
		Increases NS3 stability[323]

Apo: Apolipoprotein; BAG: BCL2-associated athanogene; Cyp: Cyclophilin; EDEM: Endoplasmic reticulum degradation enhancer, mannosidase alpha-like; ER: Endoplasmic reticulum; ERAD: ER-associated degradation; FKBP: FK506-binding protein; GRP: Glucose-regulated protein; GW: Glycine-tryptophan; HCV: Hepatitis C virus; Hip: HSP70-interacting protein; HSC70: Heat shock cognate protein 70; HSP: Heat shock protein; IFNβ: Interferon beta; IRES: Internal ribosomal entry site; LDLR: Low-density lipoprotein receptor; MTTP: Microsomal triglyceride transfer protein; NCR: Non-coding region; NS: Non-structural; ROS: Reactive oxygen species; PDI: Protein disulfide isomerase; RC: Replication complex; SigR1: Sigma non-opioid intracellular receptor 1; TRiC/CCT: TCP-1 ring complex/chaperonin-containing TCP-1; UPR: Unfolded protein response; VLDL: Very low-density lipoprotein.