scholarly journals N1-methyladenine safeguards against aberrant RNA-protein association during proteostasis stress

2019 ◽  
Author(s):  
Marion Alriquet ◽  
Giulia Calloni ◽  
Adrían Martínez-Limón ◽  
Riccardo Delli Ponti ◽  
Gerd Hanspach ◽  
...  
Keyword(s):  
Heat Shock ◽  
Protein Aggregation ◽  
Recent Work ◽  
Mammalian Cells ◽  
Cellular Differentiation ◽  
Rna Dynamics ◽  
Adenine Methylation ◽  
Functional Consequences ◽  
Aberrant Rna

AbstractPost-transcriptional modifications of nucleotide bases can effect several aspects of mRNA function. For example, the recent work has established the role of m6A in the coordinated regulation of transcriptome turnover and translation during cellular differentiation and tumorigenesis. The levels of m1A in mRNAs reach up to 10% of those of m6A, yet the functional consequences of this modification are much less clear. Here we show that N1-methyladenine protects mRNAs against aberrant interactions during heat shock and amyloidogenesis in mammalian cells. The m1A methylation motif correlated with the enhanced sequestration of transcripts in stress granules (SG). The cognate methyltransferase TRMT6/61A accumulated and m1A was enriched in SG. Downregulation of the catalytic subunit TRMT61A enhanced amyloidogenesis in the cytosol and increased bystander protein and RNA co-aggregation with Aβ aggregates. Faulty granulation of mutant RNAs has been implicated in pathogenesis of protein aggregation disorders. Our results demonstrate that also normal mRNAs succumb to co-aggregation with proteins if RNA dynamics during stress is disturbed due to the insufficient N1-adenine methylation.

Poly(ADP-ribosyl)ation regulates heat shock factor-1 activity and the heat shock response in murine fibroblasts

2006 ◽  
Vol 84 (5) ◽  
pp. 703-712 ◽  
Author(s):  
Silvia Fossati ◽  
Laura Formentini ◽  
Zhao-Qi Wang ◽  
Flavio Moroni ◽  
Alberto Chiarugi
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Heat Shock Factor ◽  
Binding Motif ◽  
Heat Shock Factor 1 ◽  
Shock Response ◽  
Parp 1

Poly(ADP-ribose) polymerase-1 (PARP-1)-dependent poly(ADP-ribose) formation is emerging as a key regulator of transcriptional regulation, even though the targets and underlying molecular mechanisms have not yet been clearly identified. In this study, we gathered information on the role of PARP-1 activity in the heat shock response of mouse fibroblasts. We show that DNA binding of heat shock factor (HSF)-1 was impaired by PARP-1 activity in cellular extracts, and was higher in PARP-1−/− than in PARP-1+/+ cells. No evidence for HSF-1 poly(ADP-ribosyl)ation or PARP-1 interaction was found, but a poly(ADP-ribose) binding motif was identified in the transcription factor amino acid sequence. Consistent with data on HSF-1, the expression of heat-shock protein (HSP)-70 and HSP–27 was facilitated in cells lacking PARP-1. Thermosensitivity, however, was higher in PARP-1−/− than in PARP-1+/+ cells. Accordingly, we report that heat-shocked PARP-1 null fibroblasts showed an increased activation of proapoptotic JNK and decreased transcriptional efficiency of prosurvival NF-κB compared with wild-type counterparts. The data indicate that poly(ADP-ribosyl)ation finely regulates HSF-1 activity, and emphasize the complex role of PARP-1 in the heat-shock response of mammalian cells.

scholarly journals The p97-UBXN1 complex regulates aggresome formation

2020 ◽  
Author(s):  
Sirisha Mukkavalli ◽  
Jacob Aaron Klickstein ◽  
Betty Ortiz ◽  
Peter Juo ◽  
Malavika Raman
Keyword(s):  
Protein Aggregation ◽  
Mammalian Cells ◽  
Proteasome Inhibition ◽  
Adaptor Proteins ◽  
Ubiquitin Proteasome System ◽  
Aaa Atpase ◽  
Evolutionarily Conserved ◽  
Ubiquitin Proteasome ◽  
Aggresome Formation

AbstractThe recognition and disposal of misfolded proteins are essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. It is presently unclear how diverse disease-relevant aggregates are recognized and processed for degradation. The p97 AAA-ATPase in combination with a host of adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the ubiquitin-proteasome system or through autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear given the large number of pathways that rely on p97 function. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes which are membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates both aggresome formation and clearance in proteasome-inhibited cells. We identify a novel and specific role for the p97 adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to ubiquitin-positive aggresomes and UBXN1 knockout cells are unable to form a single aggresome, and instead display dispersed ubiquitin aggregates. Furthermore, loss of p97-UBXN1 results in the increase in Huntingtin polyQ aggregates both in mammalian cells as well as in a C.elegans model of Huntington’s Disease. Together our work identifies evolutionarily conserved roles for p97 and its adaptor UBXN1 in the disposal of protein aggregates.

scholarly journals ELUCIDATING THE ROLE OF SMALL HEAT SHOCK PROTEIN 25 IN PROTEIN AGGREGATION

2018 ◽  
Vol 2 (suppl_1) ◽  
pp. 99-99
Author(s):  
C Carroll ◽  
A Encarnacion ◽  
M Khan ◽  
A Fisher ◽  
K Rodriguez
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Protein Aggregation ◽  
Small Heat Shock Protein

scholarly journals The p97-UBXN1 complex regulates aggresome formation

2021 ◽  
pp. jcs.254201
Author(s):  
Sirisha Mukkavalli ◽  
Jacob Aaron Klickstein ◽  
Betty Ortiz ◽  
Peter Juo ◽  
Malavika Raman
Keyword(s):  
Protein Aggregation ◽  
Mammalian Cells ◽  
Inclusion Bodies ◽  
Proteasome Inhibition ◽  
Adaptor Proteins ◽  
Cellular Homeostasis ◽  
Aaa Atpase ◽  
Evolutionarily Conserved ◽  
Aggresome Formation

The recognition and disposal of misfolded proteins is essential for the maintenance of cellular homeostasis. Perturbations in the pathways that promote degradation of aberrant proteins contribute to a variety of protein aggregation disorders broadly termed proteinopathies. The p97 AAA-ATPase in combination with adaptor proteins functions to identify ubiquitylated proteins and target them for degradation by the proteasome or autophagy. Mutations in p97 cause multi-system proteinopathies; however, the precise defects underlying these disorders are unclear. Here, we systematically investigate the role of p97 and its adaptors in the process of formation of aggresomes, membrane-less structures containing ubiquitylated proteins that arise upon proteasome inhibition. We demonstrate that p97 mediates aggresome formation and clearance and identify a novel role for the adaptor UBXN1 in the process of aggresome formation. UBXN1 is recruited to aggresomes and UBXN1 knockout cells are unable to form aggresomes. Loss of p97-UBXN1 results in increased Huntingtin polyQ inclusion bodies both in mammalian cells as well as in a C.elegans model of Huntington's Disease. Together our work identifies evolutionarily conserved roles for p97-UBXN1 in the disposal of protein aggregates.

Conventional and novel PKC isoenzymes modify the heat-induced stress response but are not activated by heat shock

1998 ◽  
Vol 111 (22) ◽  
pp. 3357-3365 ◽  
Author(s):  
C.I. Holmberg ◽  
P.M. Roos ◽  
J.M. Lord ◽  
J.E. Eriksson ◽  
L. Sistonen
Keyword(s):  
Stress Response ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Mammalian Cells ◽  
Elevated Temperatures ◽  
Heat Shock Element ◽  
Post Translational Modifications ◽  
Induced Stress ◽  
Shock Response

In mammalian cells, the heat-induced stress response is mediated by the constitutively expressed heat shock transcription factor 1 (HSF1). Upon exposure to elevated temperatures, HSF1 undergoes several post-translational modifications, including inducible phosphorylation or hyperphosphorylation. To date, neither the role of HSF1 hyperphosphorylation in regulation of the transcriptional activity of HSF1 nor the signaling pathways involved have been characterized. We have previously shown that the protein kinase C (PKC) activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), markedly enhances the heat-induced stress response, and in the present study we elucidate the mechanism by which PKC activation affects the heat shock response in human cells. Our results show that several conventional and novel PKC isoenzymes are activated during the TPA-mediated enhancement of the heat shock response and that the enhancement can be inhibited by the specific PKC inhibitor bisindolylmaleimide I. Furthermore, the potentiating effect of TPA on the heat-induced stress response requires an intact heat shock element in the hsp70 promoter, indicating that PKC-responsive pathways are able to modulate the activity of HSF1. We also demonstrate that PKC is not activated by heat stress per se. These results reveal that PKC exhibits a significant modulatory role of the heat-induced stress response, but is not directly involved in regulation of the heat shock response.

scholarly journals The protective role of m1A during stress-induced granulation

2020 ◽  
Author(s):  
Marion Alriquet ◽  
Giulia Calloni ◽  
Adrían Martínez-Limón ◽  
Riccardo Delli Ponti ◽  
Gerd Hanspach ◽  
...  
Keyword(s):  
Heat Shock ◽  
Acute Stress ◽  
Protective Role ◽  
Rna Modification ◽  
Regulatory Function ◽  
Separation Potential ◽  
Functional Consequences ◽  
Acute Stress Response ◽  
Efficient Recovery

Abstract Post-transcriptional methylation of N6-adenine and N1-adenine can affect transcriptome turnover and translation. Furthermore, the regulatory function of N6-methyladenine (m6A) during heat shock has been uncovered, including the enhancement of the phase separation potential of RNAs. In response to acute stress, e.g. heat shock, the orderly sequestration of mRNAs in stress granules (SGs) is considered important to protect transcripts from the irreversible aggregation. Until recently, the role of N1-methyladenine (m1A) on mRNAs during acute stress response remains largely unknown. Here we show that the methyltransferase complex TRMT6/61A, which generates the m1A tag, is involved in transcriptome protection during heat shock. Our bioinformatics analysis indicates that occurrence of the m1A motif is increased in mRNAs known to be enriched in SGs. Accordingly, the m1A-generating methyltransferase TRMT6/61A accumulated in SGs and mass spectrometry confirmed enrichment of m1A in the SG RNAs. The insertion of a single methylation motif in the untranslated region of a reporter RNA leads to more efficient recovery of protein synthesis from that transcript after the return to normal temperature. Our results demonstrate far-reaching functional consequences of a minimal RNA modification on N1-adenine during acute proteostasis stress.

Thermal Protein Denaturation and Protein Aggregation in Cells Made Thermotolerant by Various Chemicals: Role of Heat Shock Proteins

1995 ◽  
Vol 219 (2) ◽  
pp. 536-546 ◽  
Author(s):  
Harm H. Kampinga ◽  
Jeanette F. Brunsting ◽  
Gerard J.J. Stege ◽  
Paul W.J.J. Burgman ◽  
Antonius W.T. Konings
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Protein Aggregation ◽  
Protein Denaturation ◽  
Shock Proteins ◽  
In Cells

MANUSCRIPT EVIDENCE FOR ALPHABET-SWITCHING IN THE WORKS OF CICERO: COMMON NOUNS AND ADJECTIVES

2018 ◽  
Vol 68 (2) ◽  
pp. 498-516
Author(s):  
Neil O'Sullivan
Keyword(s):  
Recent Work ◽  
Code Switching ◽  
Consistent Pattern ◽  
Current Interest ◽  
Reliable Transmission ◽  
Accurate Record ◽  
The Way

Of the hundreds of Greek common nouns and adjectives preserved in our MSS of Cicero, about three dozen are found written in the Latin alphabet as well as in the Greek. So we find, alongside συμπάθεια, also sympathia, and ἱστορικός as well as historicus. This sort of variation has been termed alphabet-switching; it has received little attention in connection with Cicero, even though it is relevant to subjects of current interest such as his bilingualism and the role of code-switching and loanwords in his works. Rather than addressing these issues directly, this discussion sets out information about the way in which the words are written in our surviving MSS of Cicero and takes further some recent work on the presentation of Greek words in Latin texts. It argues that, for the most part, coherent patterns and explanations can be found in the alphabetic choices exhibited by them, or at least by the earliest of them when there is conflict in the paradosis, and that this coherence is evidence for a generally reliable transmission of Cicero's original choices. While a lack of coherence might indicate unreliable transmission, or even an indifference on Cicero's part, a consistent pattern can only really be explained as an accurate record of coherent alphabet choice made by Cicero when writing Greek words.

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