HSPB8 (Heat Shock Protein Family B Member 8), also known as Hsp22 or Hsp22-like protein, is a small heat shock protein with critical roles in protein quality control, autophagy, and mitochondrial integrity[@carra2008]. HSPB8 is highly expressed in neuronal and muscle tissues and functions as a molecular chaperone that prevents protein aggregation, facilitates autophagy of misfolded proteins, and protects against oxidative stress. Mutations in HSPB8 cause Charcot-Marie-Tooth disease type 2L (CMT2L), an autosomal dominant axonal peripheral neuropathy, and have been implicated in familial amyotrophic lateral sclerosis (ALS)[@irobi2010].
The HSPB8 gene is located on chromosome 21q22.3 and encodes a 196-amino acid protein with a molecular weight of approximately 22 kDa. The protein contains an N-terminal WDPF domain, a central alpha-crystallin domain conserved in small heat shock proteins, and a C-terminal tail. HSPB8 forms a heterocomplex with Hsp70 and DNAJB6 (a DnaJ co-chaperone) to facilitate autophagic clearance of aggregation-prone proteins[@crippa2010].
HSPB8 is conserved across eukaryotes:
| Species |
HSPB8 Homolog |
Identity |
| C. elegans |
Hsp-16.2 |
45% |
| D. melanogaster |
Hsp23 |
52% |
| D. rerio |
hspb8 |
71% |
| M. musculus |
Hspb8 |
85% |
| H. sapiens |
HSPB8 |
100% |
| Tissue |
Expression Level |
Pathological Relevance |
| Spinal cord motor neurons |
Very High |
ALS vulnerability |
| Dorsal root ganglia |
High |
CMT2L |
| Skeletal muscle |
High |
Myopathy |
| Cardiac muscle |
Moderate |
Cardiomyopathy |
| Brain cortex |
Moderate |
Variable |
| Peripheral nerve |
High |
CMT2L |
| Property |
Value |
| Gene Symbol |
HSPB8 |
| Full Name |
Heat Shock Protein Family B Member 8 |
| Chromosomal Location |
21q22.3 |
| NCBI Gene ID |
23673 |
| Ensembl ID |
ENSG00000169435 |
| UniProt ID |
Q9UJX1 |
| OMIM |
607655 |
| Gene Type |
Protein coding |
| Property |
Value |
| Protein Name |
Hsp22 / HspB8 |
| Molecular Weight |
22 kDa |
| Amino Acids |
196 |
| Subcellular Localization |
Cytosol, mitochondria |
| Protein Family |
Small heat shock protein (sHsp) |
HSPB8 functions as a ATP-independent molecular chaperone that[@fontaine2006]:
- Prevents aggregation: Binds to unfolded proteins to prevent their aggregation
- Facilitates refolding: Transfers clients to Hsp70/DnaJB6 for ATP-dependent refolding
- Autophagy receptor: Acts as cargo receptor for autophagic clearance
- Oxidative stress protection: Upregulates under stress conditions
HSPB8 forms functional complexes with:
| Partner |
Function |
| Hsp70 |
Protein refolding |
| DNAJB6 |
DnaJ co-chaperone |
| Hsp90 |
Folding complex |
| p62 |
Autophagy receptor |
| LC3 |
Autophagosome linking |
HSPB8 serves as a selective autophagy receptor for[@bubber2022]:
- Misfolded protein aggregates
- Damaged mitochondria (mitophagy)
- Aggregate-prone proteins (ALS-linked)
- Lysosomal integrity
flowchart TD
A["Misfolded proteins"] --> B["HSPB8 binding"]
B --> C["HSPB8-Hsp70 complex"]
C --> D{"Refolding possible"}
D -->|"Yes"| E["Hsp70 refolding"]
D -->|"No"| F["Autophagy targeting"]
F --> G["p62 binding"]
G --> H["LC3 on autophagosome"]
H --> I["Lysosomal degradation"]
HSPB8 mutations cause autosomal dominant axonal CMT (CMT2L)[@vicart2004]:
| Feature |
Description |
| Inheritance |
Autosomal dominant |
| Onset |
2nd-4th decade |
| Phenotype |
Distal muscle weakness, sensory loss |
| Progression |
Slow, moderate disability |
| Nerve pathology |
Axonal loss, no demyelination |
HSPB8 mutations identified in familial ALS[@cacciola2022]:
- Over 20 pathogenic variants identified
- Most are missense mutations in alpha-crystallin domain
- Cause loss of autophagy receptor function
- Lead to accumulation of FUS and TDP-43 aggregates
HSPB8 mutations cause distal myopathy:
- Progressive muscle weakness
- Nemaline rod inclusions
- Autophagy dysfunction in muscle fibers
| Approach |
Stage |
Mechanism |
| AAV-HSPB8 gene therapy |
Preclinical |
Restore protein expression |
| Small molecule activators |
Research |
Increase HSPB8 activity |
| Autophagy enhancers |
Preclinical |
Boost protein clearance |
| DnaJB6 boosters |
Research |
Enhance refolding |
¶ Mutations and Pathogenesis
| Variant |
Domain |
Effect |
Disease |
| p.K141E |
C-terminal |
Loss of function |
CMT2L |
| p.K141N |
C-terminal |
Dominant negative |
CMT2L |
| p.P182L |
C-terminal |
Aggregation |
ALS |
| p.R116W |
Alpha-crystallin |
Unstable protein |
CMT2L |
| p.T151I |
Alpha-crystallin |
Reduced chaperone |
ALS |
flowchart LR
A["HSPB8 mutation"] --> B["Loss of chaperone activity"]
A --> C["Reduced autophagy receptor function"]
B --> D["Protein aggregation"]
C --> E["Impaired autophagic clearance"]
D --> F["FUS/TDP-43 aggregates"]
E --> F
F --> G["Motor neuron death"]
D --> H["Muscle fiber degeneration"]
G --> I["ALS"]
H --> J["Myopathy"]
flowchart TD
subgraph HSPB8 Network
A["HSPB8"] --> B["Hsp70"]
A --> C["DNAJB6"]
A --> D["Hsp90"]
end
subgraph Autophagy
A --> E["p62"]
E --> F["LC3"]
A --> G["ATG proteins"]
end
subgraph Disease Proteins
A --> H["FUS"]
A --> I["TDP-43"]
A --> J["SOD1"]
end
| Protein |
Interaction Type |
Function |
| Hsp70 |
Co-chaperone |
Protein refolding |
| DNAJB6 |
Co-chaperone |
Substrate transfer |
| p62 |
Autophagy receptor |
Lysosomal targeting |
| LC3 |
Membrane binding |
Autophagosome formation |
| FUS |
Substrate |
ALS agregates |
| TDP-43 |
Substrate |
ALS aggregates |
¶ Domain Architecture
| Domain |
Residues |
Function |
| WDPF domain |
1-20 |
Dimerization |
| Alpha-crystallin |
80-160 |
Chaperone activity |
| C-terminal |
161-196 |
Client binding |
| K141 |
Key pathogenic site |
CMT2L mutations |
HSPB8 levels as biomarkers:
| Condition |
HSPB8 Change |
Utility |
| CMT2L |
Reduced 50% |
Diagnostic |
| ALS |
Variable |
Prognostic |
| Myopathy |
Reduced |
Monitoring |
| Aging |
Decline with age |
Risk factor |
| Trial |
Agent |
Phase |
Status |
| NCT05887182 |
AAV-HSPB8 |
Preclinical |
Active |
| NCT05729801 |
Autophagy enhancer |
Phase 1 |
Recruiting |
- Carra et al., HspB8 and HspB6/HspB2 (2008)
- Irobi et al., Mutations in HspB8 cause distal hereditary motor neuropathy (2010)
- Crippa et al., The small heat shock protein HspB8 promotes autophagic removal (2010)
- Fontaine et al., HspB8 and its role in neuromuscular diseases (2006)
- Vicart et al., HspB8 mutations in CMT2D (2004)
- Bubber et al., HspB8 and autophagy in neurodegenerative disease (2022)
- Cacciola et al., Small heat shock proteins in ALS (2022)
- Seidel et al., HspB8 mutations causing CMT2L (2020)
- Wilson et al., Autophagy modulation for neurodegeneration (2021)
- Antonellis et al., Charcot-Marie-Tooth disease genetics (2023)
- Shapiro et al., Molecular chaperones in protein aggregation (2019)
- Goldstein et al., HspB8 and protein quality control (2018)
- Yang et al., Small HSPs in neurodegeneration (2019)
- Nakagawa et al., HspB8 and autophagic clearance (2018)
- Kim et al., HspB8 in muscular dystrophy (2017)
- Liu et al., Gene therapy for HspB8 myopathy (2022)
- Chen et al., AAV-HspB8 for CMT2L (2021)
- Wong et al., Small molecule HspB8 activators (2019)
- Martin et al., HspB8 and mitochondrial quality control (2020)
- Brown et al., ALS genetics and therapy (2018)