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Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

  • Chapter
Alpha-1 Antitrypsin

Part of the book series: Respiratory Medicine ((RM))

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Abstract

A protein adopts numerous energetic folding states controlling its stability and functional trajectory during its lifespan. These states are differentially recognized and managed by a sophisticated network mainly composed of folding chaperones (the chaperome) and degradative (ubiquitin and autophagy–lysosome based) components referred to as proteostasis. The proteostasis network (PN) defines different quinary states (Q-states) for each protein in response to its secondary, tertiary, and quaternary levels of organization and hence constitutes an adaptive proteostatic landscape (APL). The APL concept emphasizes not only the dynamic and sculptable in vivo folding energy of each protein but also the dynamic function defined by the local PN. Inherited genetic disorders, such as the Z-variant in alpha-1 antitrypsin deficiency (AATD), expand the diversity of protein folding landscape excursions and often redirect the misfolded species in ways that challenge cellular, tissue, and host PN buffering and capacity. Individual-specific inherited genetic traits (Marciniak and Lomas, Clin Chest Med. 35(1):29–38, 2014), acquisition of modifiers, and environmental stressors that impair the normal PN response to misfolding excursions lead to further imbalances in the APL in both the liver and lung of AATD patients, triggering disease phenotypes. Here, we review how the PN responds to the proteostatic problem in AATD and discuss the rationale behind potential new therapeutic proteostatic strategies to manage the APL and restore the resilience and health in AATD.

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Abbreviations

PN:

Proteostasis network

ER:

Endoplasmic reticulum

AAT:

Alpha-1 antitrypsin

Q-state:

Quinary state

APL:

Adaptive proteostatic landscape

AATD:

Alpha-1 antitrypsin deficiency

NE:

Neutrophil elastase

COPD:

Chronic obstructive pulmonary disease

RCL:

Reactive center loop

WT:

Wild-type

COPII:

Coatomer protein complex II

G/ERAD:

Glycan ER-associated degradation

ER-phagy:

ER-associated autophagy response

BAL:

Bronchoalveolar lavage

HSR:

Heat shock response

UPR:

Unfolded protein response

MSR:

Maladaptive stress response

ERAF:

ER-assisted folding and glycosylation

QC:

Quality control

NEF:

Nucleotide exchange factors

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitor

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Acknowledgements

This work was supported by grants from National Institute of Health GM33301 and GM42336 for WEB, TRDRP 21XT-0070. CW is supported by postdoctoral research fellowship from Alpha-1 Foundation.

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  1. Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, San Diego, CA, 92037, USA

    Chao Wang & William E. Balch

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  1. Chao Wang
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Correspondence to William E. Balch .

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  1. University of Miami Miller School of Medicine, Miami, Florida, USA

    Adam Wanner

  2. National Jewish Health , DENVER, Colorado, USA

    Robert A. Sandhaus

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Wang, C., Balch, W.E. (2016). Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency. In: Wanner, A., Sandhaus, R. (eds) Alpha-1 Antitrypsin. Respiratory Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-23449-6_4

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