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Physiological and Pathological Functions of Cysteine Cathepsins

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Proteases in Physiology and Pathology

Abstract

Cysteine cathepsins are lysosomal hydrolases that belong to the papain family of cysteine proteases. This group comprises of 11 members and a majority of them are endo-proteases. They are initially synthesized as inactive zymogens, which are then processed into their active forms in the acidic and reducing environment of the lysosomes. The most striking element of cysteine cathepsins is their active site that contains a catalytic triad of a cysteine, histidine, and an asparagine residue. Originally, turnover and degradation of intracellular proteins was considered the only function of cysteine cathepsins. However, substantial evidences accumulated over the years have established their role in several physiological and pathological processes. Tissue-specific distribution and gene knockout analysis of these housekeeping proteases established their several physiological functions including antigen presentation, bone and tissue remodeling, keratinocyte differentiation, extracellular matrix degradation, cell cycle regulation, and death. Expression and activity of these proteases are tightly regulated, and their deregulation has been reported in a variety of pathological conditions such as cancer, lung diseases, metabolic disorders, atherosclerosis, cardiomyopathy, rheumatoid arthritis, osteoporosis, etc. These proteases have been proposed to be potential drug targets, and some of their inhibitors are under phase I clinical trial. This chapter presents an overview of the structure, synthesis, mode of action, regulation of expression and activity, and physiological as well as pathological role of lysosomal cysteine cathepsins.

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Abbreviations

&::

and

APCs::

Antigen-presenting cells

BALF::

Bronchoalveolar lavage fluid

bFGF::

Basic fibroblast growth factor

CLIP::

Class II-associated invariant chain

COPD::

Chronic obstructive pulmonary disease

cTEC::

Cortical thymus epithelial cells

DPPI::

Dipeptidyl aminopeptidase I

ECM::

Extracellular matrix

EMT::

Epithelial-mesenchymal transition

ER::

Endoplasmic reticulum

Ets::

Erythroblast transformation-specific transcription factor

GAGs::

Glycosaminoglycans

hCATL::

human cathepsin L

HMWK::

High-molecular-weight kininogens

IFN::

Interferon

IL::

Interleukin

IR::

Insulin receptor

IRES::

Internal ribosomal entry site

L::

Left-hand domain

LMP::

Lysosomal membrane permeabilization

LMWK::

Low-molecular-weight kininogens

M6PR::

Mannose-6-phosphate receptor

MMPs::

Matrix metalloproteinases

MOMP::

Mitochondrial outer membrane permeabilization

PAI::

Plasminogen activator inhibitor

R::

Right-hand domain

ROS::

Reactive oxygen species

SMA::

Smooth muscle actin

TGF::

Transforming growth factor

TGN::

Trans-Golgi network

TIMP::

Tissue inhibitors of metalloproteinases

TNF::

Tumor necrosis factor

UTR::

Untranslated regions

VEGF::

Vascular endothelial growth factor

XIAP::

X-chromosome-linked inhibitor of apoptosis

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The authors declared no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

    Mansi Manchanda, Nishat Fatima & Shyam Singh Chauhan

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  1. Mansi Manchanda
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  2. Nishat Fatima
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  3. Shyam Singh Chauhan
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Correspondence to Shyam Singh Chauhan .

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  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. St. Boniface Hospital Research Centre, University of Manitoba, Faculty of Health Sciences, College of Medicine, Institute of Cardiovascular Sciences, Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla

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Manchanda, M., Fatima, N., Chauhan, S.S. (2017). Physiological and Pathological Functions of Cysteine Cathepsins. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Physiology and Pathology. Springer, Singapore. https://doi.org/10.1007/978-981-10-2513-6_11

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