HSPA8

Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a is_associated_with::heat shock protein that in humans is encoded by the HSPA8 is_associated_with::gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging.

Function
The heat shock protein 70 (is_associated_with::Hsp70) family contains both heat-inducible and constitutively expressed members. The latter are called heat-shock cognate (Hsc) proteins. The heat shock 70 kDa protein 8 also known as Hsc70 belongs to the heat-shock cognate subgroup. This protein binds to nascent polypeptides to facilitate correct is_associated_with::protein folding. In order to properly fold non-native proteins, Hsp70 chaperones interact with the hydrophobic peptide segments of proteins in an ATP-controlled fashion. Though the exact mechanism still remains unclear, there are at least two alternative modes of action: kinetic partitioning and local unfolding. In kinetic partitioning, Hsp70s repetitively bind and release substrates in cycles that maintain low concentrations of free substrate. This effectively prevents aggregation while allowing free molecules to fold to the native state. In local unfolding, the binding and release cycles induce localized unfolding in the substrate, which helps to overcome kinetic barriers for folding to the native state. Ultimately, its role in protein folding contributes to its function in signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation.

Hsc70 additionally serves as a positive regulator of cell cycle transition and carcinogenesis. For example, Hsc70 regulates the nuclear accumulation of cyclin D1, which is a key player in G1 to S phase cell cycle transition.

Another function of Hsc70 is as an is_associated_with::ATPase in the disassembly of is_associated_with::clathrin-coated vesicles during transport of membrane components through the cell. It works with auxilin to remove is_associated_with::clathrin coated vesicles. In neurons, is_associated_with::synaptojanin is also an important protein involved in vesicle uncoating. Two alternatively spliced variants have been characterized to date.

Hsc70 is a key component of is_associated_with::chaperone-mediated autophagy wherein it imparts selectivity to the proteins being degraded by this lysosomal pathway.

Hsc70 vs Hsp70 comparison
Human Hsc70 has 85% identity with human Hsp70 (SDSC workbench, blosom26 default analysis). The scientific community has long assumed that Hsp70 and Hsc70 have similar cellular roles, but this assumption proved erroneous.

Unlike canonical heat shock proteins, Hsc70 is constitutively expressed and performs functions related to normal cellular processes. Hsc70 was placed in the heat shock protein family due to homology with other heat shock proteins.

Clinical significance
Hsp70 member proteins, including Hsp72, inhibit apoptosis by acting on the caspase-dependent pathway and against apoptosis-inducing agents such as tumor necrosis factor-α (TNFα), staurosporin, and doxorubicin. This role leads to its involvement in many pathological processes, such as oncogenesis, neurodegeneration, and senescence. In particular, overexpression of HSP72 has been linked to the development some cancers, such as hepatocellular carcinoma, gastric cancers, colonic tumors, breast cancers, and lung cancers, which led to its use as a prognostic marker for these cancers. Elevated Hsp70 levels in tumor cells may increase malignancy and resistance to therapy by complexing, and hence, stabilizing, oncofetal proteins and products and transporting them into intracellular sites, thereby promoting tumor cell proliferation. As a result, tumor vaccine strategies for Hsp70s have been highly successful in animal models and progressed to clinical trials. One treatment, a Hsp72/AFP recombined vaccine, elicited robust protective immunity against AFP-expressing tumors in mice experiments. Therefore, the vaccine holds promise for treating hepatocellular carcinoma. Alternatively, overexpression of Hsp70 can mitigate the effects of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s corea, and spinocerebellar ataxias, and aging and cell senescence, as observed in centenarians subjected to heat shock challenge. In particular, Hsc70 plays a protective role in the aforementioned diseases, as well as in other neuropsychiatric disorders such as schizophrenia.

Interactions
HSPA8 has been shown to interact with:


 * is_associated_with::BAG1,
 * is_associated_with::BAG2,
 * is_associated_with::BAG3,
 * is_associated_with::BAG4,
 * is_associated_with::CDC5L,
 * is_associated_with::CITED1,
 * CCND1,
 * is_associated_with::DNAJA3,
 * is_associated_with::GJA1,
 * is_associated_with::HSPBP1,
 * PARK2, and
 * is_associated_with::STUB1.