Transient Aggregation of Ubiquitinated Proteins Is a Cytosolic Unfolded Protein Response to Inflammation and Endoplasmic Reticulum Stress

Liu, Xian De; Ko, Soyoung; Xu, Yi; Fattah, Elmoataz Abdel; Xiang, Qian; Jagannath, Chinnaswamy; Ishii, Tetsuro; Komatsu, Masaaki; Eissa, N. Tony

doi:10.1074/jbc.m112.350934

Cited by 87 publications

(83 citation statements)

References 48 publications

(49 reference statements)

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“…These data are consistent with previous findings that demonstrate a substantial increase in ubiquitinated proteins in severely emphysematous human lung tissue sections (9,12). Similar dysfunctional proteostatic mechanisms have also been implicated in the pathogenesis of CS-induced chronic bronchitis, which involves the aggresomal sequestration of cystic fibrosis transmembrane conductance regulator (CFTR) (76,83,84) and in other chronic lung diseases such as α1-antitrypsin deficiency (A1AD) and pulmonary fibrosis (5). We conclude that certain features of our in vitro and in vivo findings were corroborated in human clinical samples, namely that patients with COPD displayed increased HDAC6 expression and evidence for proteopathy in addition to elevated autophagy, as previously described (10,11).…”

Section: Figure 10supporting

confidence: 92%

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Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1 +/-or Map1lc3B -/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6 -/Y ) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1 -/-, Map1lc3B -/-, and Hdac6 -/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.

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Section: Figure 10supporting

confidence: 92%

“…The autophagic pathway is known to act as a compensatory mechanism for protein degradation under conditions of impaired proteasomal activity, which can be induced by CS (36,76). The accumulation of CS-denatured proteins in aggresomes in excess of cellular degradative capacity may represent a harmful intermediate state.…”

Section: Figure 10mentioning

confidence: 99%

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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“…7C, E and 8D). The accumulating aggresomes in turn might provoke an independent stress signal, potentially sensed and transduced by the cargo receptors SQSTM1 and NBR1 who have been suggested to play a signaling role, 57,58 and act in concert with the ER stress-activated ERN1-MAPK8-BCL2-BECN1 pathway to stimulate ULK1 and initiate the autophagy cascade. More studies are needed to clarify the detailed mechanism to answer this interesting question.…”

Section: Different Mechanisms Mediate Starvation-and Proteasome Inhibmentioning

confidence: 99%

“…An intriguing possibility is that there might exist an "aggregate sensor," potentially the cargo receptors SQSTM1 and NBR1 who have been postulated to play additional signaling roles, 57,58 in the selective autophagy pathway that facilitates the interaction between polymerized cargos and the autophagosome. It is equally likely that the cargo in its polymerized form can directly facilitate autophagosomal assembly and sequestration, as has been proposed for the dodecamer prApe1 in the yeast Cvt pathway.…”

Section: Proteasome Inhibition Induces a Cvt-like Autophagy Response mentioning

confidence: 99%

The GST-BHMT assay reveals a distinct mechanism underlying proteasome inhibition-induced macroautophagy in mammalian cells

Rui

Chen

et al. 2015

Autophagy

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#These authors equally contributed to this work.Keywords: BHMT, cargo receptors SQSTM1/p62 and NBR1, MTOR, PRKAA/AMPK, proteasome inhibition, selective macroautophagyAbbreviations: ACACA/B, acetyl-CoA carboxylase a/b; ACTB, actin, b; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; ATG7, autophagy-related 7; Baf A1, bafilomycin A 1 ; BCL2, B-cell CLL/lymphoma 2; BECN1, Beclin 1, autophagy-related; BHMT, betaine-homocysteine S-methyltransferase; CTNNB1, catenin (cadherin-associated protein), b 1, 88kDa; Cvt, cytoplasm-to-vacuole-targeting; DDIT3, DNA-damage-inducible transcript 3; EBSS, Earle's Balanced Salt Solution; EIF2AK3, eukaryotic translation initiation factor 2-a, kinase 3; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; ERN1, endoplasmic reticulum to nucleus signaling 1; GST, glutathionine S-transferase; GST-BHMT, a fusion protein of glutathionine S-transferase N-terminal to betaine-homocysteine S-methyltransferase; GST-BHMT (FRAG) , an autophagy-mediated cleavage product of the GST-BHMT reporter; HA, hemagglutinin; HSPA5, heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa); LSCS, linker-specific cleavage site; MAP1LC3, microtubule-associated protein 1 light chain 3; MAP2K7, mitogen-activated protein kinase kinase 7; MAPK8, mitogen-activated protein kinase 8; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, MTOR complex 1; NBR1, neighbor of BRCA1 gene 1; P4HB, prolyl 4-hydroxylase, b polypeptide; PRKAA, protein kinase, AMP-activated, a catalytic subunit; RHEB, Ras homolog enriched in brain; RM, rich medium; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TSC1/2, tuberous sclerosis 1/2; ULK1, unc-51 like autophagy activating kinase 1; UPR, unfolded protein response; UPS, ubiquitin proteasome system; XBP1, X-box binding protein 1By monitoring the fragmentation of a GST-BHMT (a protein fusion of glutathionine S-transferase N-terminal to betaine-homocysteine S-methyltransferase) reporter in lysosomes, the GST-BHMT assay has previously been established as an endpoint, cargo-based assay for starvation-induced autophagy that is largely nonselective. Here, we demonstrate that under nutrient-rich conditions, proteasome inhibition by either pharmaceutical or genetic manipulations induces similar autophagy-dependent GST-BHMT processing. However, mechanistically this proteasome inhibition-induced autophagy is different from that induced by starvation as it does not rely on regulation by MTOR (mechanistic target of rapamycin [serine/threonine kinase]) and PRKAA/AMPK (protein kinase, AMP-activated, a catalytic subunit), the upstream central sensors of cellular nutrition and energy status, but requires the presence of the cargo receptors SQSTM1/p62 (sequestosome 1) and NBR1 (neighbor of BRCA1 gene 1) that are normally involved in the selective autophagy pathway. Further, it depends on ER (endoplasmic reticulum) stress signaling, in particular ERN1/IRE1 (endoplasmic ...

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“…Concomitant TPEF imaging of these endogenous biochemicals can elucidate proteostasis in cells (i.e., transient aggregation of ubiquitinated proteins and etc.) [11]. Although the optical properties (e.g., scattering) change was assumed to be related to the coagulation of intracellular proteins during acetowhitening process in cells [12], no experimental proofs have been reported yet.…”

Section: Introductionmentioning

confidence: 99%

Multimodal nonlinear optical microscopic imaging provides new insights into acetowhitening mechanisms in live mammalian cells without labeling

Jun

Teh

Zheng

et al. 2014

Biomed. Opt. Express

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Abstract:We developed a multimodal nonlinear optical microscopy imaging (e.g., third-harmonic generation (THG) and two-photon excited fluorescence (TPEF)) platform based on a femtosecond laser pumped photonic crystal fiber to investigate the acetowhitening phenomenon induced by acetic acid in live mammalian cells without labeling. After treated by acetic acid with concentrations of higher than 0.2%, THG images show that light scattering is remarkably increased inside the nucleus and cytoplasm in cells. Co-localized TPEF and THG imaging on tryptophan and NADH in cells indicates that the change of scattering property is largely originating from the morphological change of metabolic proteins induced by acetic acids. Further TPEF imaging on NADH and FAD in cells confirms that this change is irreversible when acetic acid concentration is higher than 1.2%. These subcellular-level THG/TPEF imaging results reveal that the acetowhitening phenomenon is highly related with proteins involved in metabolic pathways in the nucleus and cytoplasm in live cells.

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Transient Aggregation of Ubiquitinated Proteins Is a Cytosolic Unfolded Protein Response to Inflammation and Endoplasmic Reticulum Stress

Cited by 87 publications

References 48 publications

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

The GST-BHMT assay reveals a distinct mechanism underlying proteasome inhibition-induced macroautophagy in mammalian cells

Multimodal nonlinear optical microscopic imaging provides new insights into acetowhitening mechanisms in live mammalian cells without labeling

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