Disruption of the Chaperonin Containing TCP-1 Function Affects Protein Networks Essential for Rod Outer Segment Morphogenesis and Survival

Posokhova, Ekaterina; Song, Hailong; Belcastro, Marycharmain; Higgins, Lee Ann; Bigley, Lauren R.; Michaud, Norman; Martemyanov, Kirill A.; Sokolov, Maxim

doi:10.1074/mcp.m110.000570

Cited by 33 publications

(36 citation statements)

References 42 publications

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“…S2). Such a CCT "jamming" may eventually cause cell death, similarly to that in rods expressing the dominant negative PhLP mutant (19). Given that the ubiquitin-proteasome system plays a critical role in intracellular degradation of both Gprotein βγ-complexes and unfolded Gβ subunits (20,21), it is likely that the bulk of Gβ 1 synthetized in Gγ 1 −/− rods is eventually targeted to proteasomes, either directly or following a stage of CCT association (Fig.…”

Section: Resultsmentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Inherited retinal degenerations, caused by mutations in over 100 individual genes, affect approximately 2 million people worldwide. Many of the underlying mutations cause protein misfolding or mistargeting in affected photoreceptors. This places an increased burden on the protein folding and degradation machinery, which may trigger cell death. We analyzed how these cellular functions are affected in degenerating rods of the transducin γ-subunit (Gγ 1 ) knockout mouse. These rods produce large amounts of transducin β-subunit (Gβ 1 ), which cannot fold without Gγ 1 and undergoes intracellular proteolysis instead of forming a transducin βγ-subunit complex. Our data revealed that the most critical pathobiological factor leading to photoreceptor cell death in these animals is insufficient capacity of proteasomes to process abnormally large amounts of misfolded protein. A decrease in the Gβ 1 production in Gγ 1 knockout rods resulted in a significant reduction in proteasomal overload and caused a striking reversal of photoreceptor degeneration. We further demonstrated that a similar proteasomal overload takes place in photoreceptors of other mutant mice where retinal degeneration has been ascribed to protein mistargeting or misfolding, but not in mice whose photoreceptor degenerate as a result of abnormal phototransduction. These results establish the prominence of proteasomal insufficiency across multiple degenerative diseases of the retina, thereby positioning proteasomes as a promising therapeutic target for treating these debilitating conditions. neurodegenerative diseases | protein degradation

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Section: Resultsmentioning

confidence: 99%

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Lobanova

Finkelstein

Skiba

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Some of the proteins had been previously shown to interact with HDAC6, such as b tubulin and its network 29 and the molecular chaperones HSP90 and GRP78/HSPA5. 30 Other components of the HDAC6 interactome that were newly characterised in this study and occurred repeatedly across different mass spectrometry analyses included the chaperonin TCP1 complex, 31 DNA repair proteins like Ku80/XRCC5, PCNA, and MSH2, 32 components of the proteasome like PSMD1 (26S proteasome regulatory subunit 1) and metabolic enzymes, like PCK1 (phosphoenolpyruvate carboxykinase 1), suggesting that HDAC6 has the potential to influence a number of different protein networks, and perhaps DNA repair (Figure 5d). These interactions were similarly evident in the inducible HDAC6 stable cells under immunoprecipitation conditions, for example, between HDAC6 and HSP90, GRP78 and Ku80 (Figures 5e and f).…”

Section: Hr23b Influences Autophagymentioning

confidence: 99%

A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors

et al. 2013

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Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment. Cell Death and Differentiation (2013) 20, 1306-1316 doi:10.1038/cdd.2013 published online 24 May 2013 Histone deacetylase is a family of enzymes that control the acetylation of chromatin.1 An increasingly large group of proteins connected with different aspects of normal and tumour cell biology are known to be influenced by acetylation.2-4 As a consequence, the HDAC family has attracted considerable attention as a therapeutic target.2,3,5 Indeed, inhibition of HDAC activity is strongly anti-proliferative on tumour cells in vitro, and delays tumour growth in xenograft models. [5][6][7] An extensive number of clinical trials with HDAC inhibitors in a variety of malignancies are underway, and two HDAC inhibitors, SAHA/Vorinostat and FK228/Romidepsin, have to date been approved for treating a human malignancy, namely cutaneous T-cell lymphoma (CTCL 1,(8)(9)(10) ). However, identifying other malignancies and disease types that are likely to respond favourably to HDAC inhibitors has been hampered, principally because knowledge of the key pathways through which HDAC inhibitors affect tumour cell growth remains limited. 9,11 In previous studies, we undertook through a genome-wide loss-of-function screen to identify genes that have an impact on the sensitivity of tumour cells to HDAC inhibitors. 12 We reasoned that genes identified in this way would not only provide important information on key pathways affected by HDAC inhibitors, but also identify potential biomarkers that inform on the tumour response to HDAC inhibitor-based therapies. 11,12 Through this analysis, we identified HR23B as a protein that influences the response and sensitivity of tumour cells to HDAC inhibitors.12 HR23B functions in at least two pathways; nucleotide excision repair (NER) and protein targeting to the proteasome. [13][14][15] Further studies suggested that the ability of HR23B to engage in proteasomal shuttling underpins its role as a determinant of HDAC inhibitor sensitivity, and it is consistent with this idea that aberrant proteasome activity occurs in tumour cells trea...

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“…Animal Models-Transgenic mice expressing ⌬1-83 PhLP-FLAG have been previously described (32). All analyses were performed using ⌬1-83 PhLP-FLAG ϩ/Ϫ and…”

Section: Methodsmentioning

confidence: 99%

Splice Isoforms of Phosducin-like Protein Control the Expression of Heterotrimeric G Proteins

Gao¹,

Sinha²,

Belcastro³

et al. 2013

Journal of Biological Chemistry

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Background: Heterotrimeric G proteins are essential for biological signaling; however, the mechanism of their biosynthesis remains poorly understood. Results: Long and short splice isoforms of phosducin-like protein stimulate and inhibit production of G proteins in the cell. Conclusion: Both G protein ␣ and ␤␥ functional units are subject to the regulation. Significance: We describe a potential mechanism for regulating the cellular levels of G proteins.

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Disruption of the Chaperonin Containing TCP-1 Function Affects Protein Networks Essential for Rod Outer Segment Morphogenesis and Survival

Cited by 33 publications

References 42 publications

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration

A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors

Splice Isoforms of Phosducin-like Protein Control the Expression of Heterotrimeric G Proteins

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