Haptoglobin acting as a Natural Inhibitor of Cathepsin B Activity

Snellman, Olle; Sylvén, Bengt

doi:10.1038/2161033a0

Cited by 56 publications

(20 citation statements)

References 5 publications

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“…Sequestration of hemoglobin by haptoglobin is an important protective mechanism that reduces the amount of free hemoglobin and iron available to catalyze oxidative reactions (78). Other proposed roles for haptoglobin include, but are not limited to, regulation of cathepsin B activity (79), angiogenesis (80) and the immune system (81). In support of the latter, haptoglobin knockout mice have lower counts of mature T and B cells and display reduced adaptive immune responses (82).…”

Section: Haptoglobinmentioning

confidence: 99%

Extracellular Chaperones and Proteostasis

Wyatt

Yerbury

Ecroyd

et al. 2013

Annu. Rev. Biochem.

161

173

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There is a family of currently untreatable serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited but has significantly advanced with the discovery of a small but growing family of constitutively secreted extracellular chaperones (ECs). The available evidence strongly suggests that these chaperones act as both sensors and disposal-mediators of misfolded proteins in extracellular fluids, thereby normally protecting us from disease pathologies. It is critically important to further increase our understanding of the mechanisms that operate to effect extracellular proteostasis, as this will be essential knowledge upon which to base the development of effective therapies for some of the world's most debilitating, costly and intractable diseases.

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Section: Haptoglobinmentioning

confidence: 99%

Extracellular Chaperones and Proteostasis

Wyatt

Yerbury

Ecroyd

et al. 2013

Annu. Rev. Biochem.

161

173

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show abstract

“…A variety of other putative functions have also been ascribed to Hp. It has been implicated in immune regulation (Louagie et al, 1993), shown to inhibit cathepsin B activity (Snellman and Sylven 1967) and to have pro-angiogenic effects (Cid et al, 1993). Binding of Hp to human neutrophils has been reported to inhibit respiratory burst activity (Oh et al, 1990).…”

Section: Haptoglobinmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…When complexed to Hb, Hp is known to be recognized by the cell surface receptors CD163 and Mac-1 and to be taken up by receptormediated endocytosis for degradation (23). Hp has also been implicated in immune regulation (24) and shown to inhibit cathepsin B activity (25). Taken together, the available evidence indicates that Hp is likely to play an important role in suppressing the inflammatory response under a variety of different conditions.…”

mentioning

confidence: 99%

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

Yerbury

Kumita

Meehan

et al. 2009

Journal of Biological Chemistry

110

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␣ 2 -Macroglobulin (␣ 2 M) and haptoglobin (Hp) are both abundant secreted glycoproteins that are best known for their protease trapping and hemoglobin binding activities, respectively. Like the small heat shock proteins, both these glycoproteins have in common the ability to protect a range of proteins from stress-induced amorphous aggregation and have been described as extracellular chaperones. Using an array of biophysical techniques, this study establishes that in vitro at substoichiometric levels and under physiological conditions ␣ 2 M and Hp both inhibit the formation of amyloid fibrils from a range of proteins. We also provide evidence that both ␣ 2 M and Hp interact with prefibrillar species to maintain the solubility of amyloidogenic proteins. These findings suggest that both ␣ 2 M and Hp are likely to play an important role in controlling the inappropriate aggregation of proteins in the extracellular environment.

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Haptoglobin acting as a Natural Inhibitor of Cathepsin B Activity

Cited by 56 publications

References 5 publications

Extracellular Chaperones and Proteostasis

Extracellular Chaperones and Proteostasis

Extracellular Chaperones and Amyloids

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

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