Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Tran, Ian; Ji, Changhoon; Ni, Inzer; Min, Taehong; Tang, Danni; Vij, Neeraj

doi:10.1165/rcmb.2014-0107oc

Cited by 99 publications

(137 citation statements)

References 79 publications

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“…In addition, we identified that clearance of these AB using an autophagy inducer carbamazepine not only reduces apoptosis but also controls cigarette smoke (CS)-induced emphysema (51). Hence, recent studies from our group and others (27,51) have identified the potential of autophagy inducer carbamazepine in rescuing both smoke-induced and alpha-1-antitrypsin Z mutation-associated emphysema in COPD.…”

Section: Innovationmentioning

confidence: 92%

“…We recently identified proteostasis/autophagy impairment as a novel central mechanism leading to aggresome formation and subsequent downstream effects such as apoptosis in COPDemphysema (41,51). We and others have identified the global impact of first-and second-hand smoke exposure on overall protein synthesis, ubiquitination, and aggregation of misfolded proteins in perinuclear spaces as aggresome bodies (AB) leading to a unique pathology associated with severity of emphysema in COPD subjects (21,23,35,51,56,58). In addition, we identified that clearance of these AB using an autophagy inducer carbamazepine not only reduces apoptosis but also controls cigarette smoke (CS)-induced emphysema (51).…”

Section: Innovationmentioning

confidence: 99%

“…We and others have identified the global impact of first-and second-hand smoke exposure on overall protein synthesis, ubiquitination, and aggregation of misfolded proteins in perinuclear spaces as aggresome bodies (AB) leading to a unique pathology associated with severity of emphysema in COPD subjects (21,23,35,51,56,58). In addition, we identified that clearance of these AB using an autophagy inducer carbamazepine not only reduces apoptosis but also controls cigarette smoke (CS)-induced emphysema (51). Hence, recent studies from our group and others (27,51) have identified the potential of autophagy inducer carbamazepine in rescuing both smoke-induced and alpha-1-antitrypsin Z mutation-associated emphysema in COPD.…”

Section: Innovationmentioning

confidence: 99%

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Airway Exposure to E-Cigarette Vapors Impairs Autophagy and Induces Aggresome Formation

Shivalingappa

Hole

Westphal

et al. 2016

Antioxidants & Redox Signaling

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Aims: Electronic cigarettes (e-cigarettes) are proposed to be a safer alternative to tobacco cigarettes. Hence, we evaluated if e-cigarette vapors (eCV) impair cellular proteostasis similar to cigarette smoke exposure. Results: First, we evaluated the impact of eCV exposure (2.5 or 7.5 mg) on Beas2b cells that showed significant increase in accumulation of total polyubiquitinated proteins (Ub, insoluble fractions) with time-dependent decrease in proteasomal activities from 1 h ( p < 0.05), 3 h ( p < 0.001) to 6 h ( p < 0.001) of eCV exposure compared to room air control. We verified that even minimal eCV exposure (1 h) induces valosin-containing protein (VCP; p < 0.001), sequestosome-1/p62 (aberrant autophagy marker; p < 0.05), and aggresome formation (total polyUb-accumulation; p < 0.001) using immunoblotting (IB), fluorescence microscopy, and immunoprecipitation (IP). The inhibition of protein synthesis by 6 h of cycloheximide (50 lg/ml) treatment significantly ( p < 0.01) alleviates eCV-induced (1 h) aggresome bodies. We also observed that eCV (1 h)-induced protein aggregation can activate oxidative stress, apoptosis (caspase-3/7), and senescence ( p < 0.01) compared to room air controls. We verified using an autophagy inducer carbamazepine (20 lM, 6 h) or cysteamine (250 lM; 6 h, antioxidant) that eCV-induced changes in oxidative stress, poly-ub-accumulation, proteasomal activity, autophagy, apoptosis, and/or senescence could be controlled by autophagy induction. We further confirmed the role of acute eCV exposure on autophagy impairment in murine lungs (C57BL/6 and CD1) by IB (Ub, p62, VCP) and IP (VCP, p62), similar to in-vitro experiments. Innovation: In this study, we report for the first time that eCV exposure induces proteostasis/autophagy impairment leading to oxidative stress, apoptosis, and senescence that can be ameliorated by an autophagy inducer. Conclusion: eCV-induced autophagy impairment and aggresome formation suggest their potential role in chronic obstructive pulmonary disease-emphysema pathogenesis.

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Section: Innovationmentioning

confidence: 92%

Section: Innovationmentioning

confidence: 99%

Section: Innovationmentioning

confidence: 99%

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Airway Exposure to E-Cigarette Vapors Impairs Autophagy and Induces Aggresome Formation

Shivalingappa

Hole

Westphal

et al. 2016

Antioxidants & Redox Signaling

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“…71 Similar to our findings in the diacetyl-exposed lung, ubiquitinated protein aggregates and the corresponding human protein, SQSTM1, accumulate in humans with chronic obstructive pulmonary disease. 72,73 Cigarette smoke is implicated in these aggregates in humans with chronic obstructive pulmonary disease. 72 Because our study demonstrates that diacetyl alters proteostasis and cigarette smoke contains diacetyl, 74,75 the results suggest that diacetyl may play a role in chronic obstructive pulmonary disease in addition to its role in flavorings-related lung disease.…”

Section: Protein Damage and Diacetyl Cytotoxicitymentioning

confidence: 99%

“…72,73 Cigarette smoke is implicated in these aggregates in humans with chronic obstructive pulmonary disease. 72 Because our study demonstrates that diacetyl alters proteostasis and cigarette smoke contains diacetyl, 74,75 the results suggest that diacetyl may play a role in chronic obstructive pulmonary disease in addition to its role in flavorings-related lung disease. 11,12 In addition, during autophagy, SQSTM1 is phosphorylated, a process that activates the Kelch-like ECHassociated protein 1 (Keap1)enuclear factor E2erelated factor 2 (Nrf2) pathway.…”

Section: Protein Damage and Diacetyl Cytotoxicitymentioning

confidence: 99%

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Hubbs

Fluharty

Edwards

et al. 2016

The American Journal of Pathology

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Inhaled diacetyl vapors are associated with flavorings-related lung disease, a potentially fatal airway disease. The reactive a-dicarbonyl group in diacetyl causes protein damage in vitro. Dicarbonyl/ L-xylulose reductase (DCXR) metabolizes diacetyl into acetoin, which lacks this a-dicarbonyl group. To investigate the hypothesis that flavorings-related lung disease is caused by in vivo protein damage, we correlated diacetyl-induced airway damage in mice with immunofluorescence for markers of protein turnover and autophagy. Western immunoblots identified shifts in ubiquitin pools. Diacetyl inhalation caused dose-dependent increases in bronchial epithelial cells with puncta of both total ubiquitin and K63-ubiquitin, central mediators of protein turnover. This response was greater in Dcxr-knockout mice than in wild-type controls inhaling 200 ppm diacetyl, further implicating the a-dicarbonyl group in protein damage. Western immunoblots demonstrated decreased free ubiquitin in airway-enriched fractions. Transmission electron microscopy and colocalization of ubiquitin-positive puncta with lysosomal-associated membrane proteins 1 and 2 and with the multifunctional scaffolding protein sequestosome-1 (SQSTM1/p62) confirmed autophagy. Surprisingly, immunoreactive SQSTM1 also accumulated in the olfactory bulb of the brain. Olfactory bulb SQSTM1 often congregated in activated microglial cells that also contained olfactory marker protein, indicating neuronophagia within the olfactory bulb. This suggests the possibility that SQSTM1 or damaged proteins may be transported from the nose to the brain. Together, these findings strongly implicate widespread protein damage in the etiology of flavorings-related lung disease. (Am J Pathol 2016, 186: 2887e2908; http://dx

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Vimentin's side gig: Regulating cellular proteostasis in mammalian systems

Morrow

Moore

2020

Cytoskeleton

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Intermediate filaments (IFs) perform a diverse set of well-known functions including providing structural support for the cell and resistance to mechanical stress, yet recent evidence has revealed unexpected roles for IFs as stress response proteins. Previously, it was shown that the type III IF protein vimentin forms cage-like structures around centrosome-associated proteins destined for degradation, structures referred to as aggresomes, suggesting a role for vimentin in protein turnover. However, vimentin's function at the aggresome has remained largely understudied. In a recent report, vimentin was shown to be dispensable for aggresome formation, but played a critical role in protein turnover at the aggresome through localizing proteostasis-related machineries, such as proteasomes, to the aggresome. Here, we review evidence for vimentin's function in proteostasis and highlight the organismal implications of these findings.

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Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Cited by 99 publications

References 79 publications

Airway Exposure to E-Cigarette Vapors Impairs Autophagy and Induces Aggresome Formation

Airway Exposure to E-Cigarette Vapors Impairs Autophagy and Induces Aggresome Formation

Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity

Vimentin's side gig: Regulating cellular proteostasis in mammalian systems

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