Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy

AbstractIn our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance.

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Lin28, a major translation reprogramming factor, gains access to YB-1-packaged mRNA through its cold-shock domain

Communications Biology ◽

10.1038/s42003-021-01862-3 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Anastasiia Samsonova ◽

Krystel El Hage ◽

Bénédicte Desforges ◽

Vandana Joshi ◽

Marie-Jeanne Clément ◽

...

Keyword(s):

Cancer Progression ◽

Cold Shock ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Binding Protein ◽

Large Set ◽

Core Component ◽

The Core ◽

Cold Shock Domain ◽

Global Translation

AbstractThe RNA-binding protein Lin28 (Lin28a) is an important pluripotency factor that reprograms translation and promotes cancer progression. Although Lin28 blocks let-7 microRNA maturation, Lin28 also binds to a large set of cytoplasmic mRNAs directly. However, how Lin28 regulates the processing of many mRNAs to reprogram global translation remains unknown. We show here, using a structural and cellular approach, a mixing of Lin28 with YB-1 (YBX1) in the presence of mRNA owing to their cold-shock domain, a conserved β-barrel structure that binds to ssRNA cooperatively. In contrast, the other RNA binding-proteins without cold-shock domains tested, HuR, G3BP-1, FUS and LARP-6, did not mix with YB-1. Given that YB-1 is the core component of dormant mRNPs, a model in which Lin28 gains access to mRNPs through its co-association with YB-1 to mRNA may provide a means for Lin28 to reprogram translation. We anticipate that the translational plasticity provided by mRNPs may contribute to Lin28 functions in development and adaptation of cancer cells to an adverse environment.

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Csde1 binds transcripts involved in protein homeostasis and controls their expression in erythropoiesis

10.1101/203497 ◽

2017 ◽

Cited By ~ 1

Author(s):

Kat S Moore ◽

Nurcan Yagci ◽

Floris van Alphen ◽

Nahuel A Paolini ◽

Rastislav Horos ◽

...

Keyword(s):

Protein Expression ◽

Mrna Expression ◽

Mrna Stability ◽

Cold Shock ◽

Rna Binding ◽

Mrna Translation ◽

Mitochondrial Respiratory Chain ◽

Protein Homeostasis ◽

Diamond Blackfan Anemia ◽

Cold Shock Domain

AbstractExpression of the RNA-binding protein Csde1 (Cold shock domain protein e1) is strongly upregulated during erythropoiesis compared to other hematopoietic lineages. In the severe congenital anemia Diamond Blackfan Anemia (DBA), however, Csde1 expression is impaired. Reduced expression of Csde1 in healthy erythroblasts impaired their proliferation and differentiation, which suggests an important role for Csde1 in erythropoiesis. To investigate the cellular pathways controlled by Csde1 in erythropoiesis, we identified the transcripts that physically associate with Csde1 in erythroid cells. These mainly encoded proteins involved in ribogenesis, mRNA translation and protein degradation, but also proteins associated with the mitochondrial respiratory chain and mitosis. Crispr/Cas9-mediated deletion of the first cold shock domain of Csde1 affected RNA expression and/or protein expression of Csde1-bound transcripts. For instance, protein expression of Pabpc1 was enhanced while Pabpc1 mRNA expression was reduced indicating more efficient translation of Pabpc1 followed by negative feedback on mRNA stability. Overall, the effect of reduced Csde1 function on mRNA stability and translation of Csde1-bound transcripts was modest. Clones with complete loss of Csde1, however, could not be generated. We suggest that Csde1 is involved in feed-back control in protein homeostasis and that it dampens stochastic changes in mRNA expression.

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piRNAs Interact with Cold-Shock Domain-Containing RNA Binding Proteins and Regulate Neuronal Gene Expression During Differentiation

Molecular Neurobiology ◽

10.1007/s12035-021-02678-2 ◽

2022 ◽

Author(s):

Charannya Sozheesvari Subhramanyam ◽

Qiong Cao ◽

Cheng Wang ◽

Zealyn Shi-Lin Heng ◽

Zhihong Zhou ◽

...

Keyword(s):

Gene Expression ◽

Binding Proteins ◽

Cold Shock ◽

Rna Binding ◽

Rna Binding Proteins ◽

Neuronal Gene ◽

Cold Shock Domain

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Cold-Shock Domains—Abundance, Structure, Properties, and Nucleic-Acid Binding

Cancers ◽

10.3390/cancers13020190 ◽

2021 ◽

Vol 13 (2) ◽

pp. 190

Author(s):

Udo Heinemann ◽

Yvette Roske

Keyword(s):

Cold Shock ◽

Rna Binding ◽

Binding Mode ◽

Nucleic Acid Binding ◽

Cold Shock Proteins ◽

Dna And Rna ◽

Promiscuous Dna ◽

Human Proteins ◽

Cold Shock Domain ◽

Shock Proteins

The cold-shock domain has a deceptively simple architecture but supports a complex biology. It is conserved from bacteria to man and has representatives in all kingdoms of life. Bacterial cold-shock proteins consist of a single cold-shock domain and some, but not all are induced by cold shock. Cold-shock domains in human proteins are often associated with natively unfolded protein segments and more rarely with other folded domains. Cold-shock proteins and domains share a five-stranded all-antiparallel β-barrel structure and a conserved surface that binds single-stranded nucleic acids, predominantly by stacking interactions between nucleobases and aromatic protein sidechains. This conserved binding mode explains the cold-shock domains’ ability to associate with both DNA and RNA strands and their limited sequence selectivity. The promiscuous DNA and RNA binding provides a rationale for the ability of cold-shock domain-containing proteins to function in transcription regulation and DNA-damage repair as well as in regulating splicing, translation, mRNA stability and RNA sequestration.

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RNA-binding strategies common to cold-shock domain- and RNA recognition motif-containing proteins

Nucleic Acids Research ◽

10.1093/nar/29.11.2223 ◽

2001 ◽

Vol 29 (11) ◽

pp. 2223-2233 ◽

Cited By ~ 42

Author(s):

X. Manival

Keyword(s):

Cold Shock ◽

Rna Binding ◽

Rna Recognition Motif ◽

Rna Recognition ◽

Recognition Motif ◽

Cold Shock Domain

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Heat stable ssDNA/RNA-binding activity of a wheat cold shock domain protein

FEBS Letters ◽

10.1016/j.febslet.2005.07.074 ◽

2005 ◽

Vol 579 (21) ◽

pp. 4887-4891 ◽

Cited By ~ 26

Author(s):

Kentaro Nakaminami ◽

Kentaro Sasaki ◽

Shinya Kajita ◽

Hisashi Takeda ◽

Dale Karlson ◽

...

Keyword(s):

Cold Shock ◽

Rna Binding ◽

Binding Activity ◽

Heat Stable ◽

Cold Shock Domain ◽

Domain Protein

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RNP-1, an RNA-binding motif is conserved in the DNA-binding cold shock domain

Nucleic Acids Research ◽

10.1093/nar/20.11.2861 ◽

1992 ◽

Vol 20 (11) ◽

pp. 2861-2864 ◽

Cited By ~ 81

Author(s):

David Landsman

Keyword(s):

Dna Binding ◽

Cold Shock ◽

Rna Binding ◽

Binding Motif ◽

Cold Shock Domain

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Solution structure of the RNA-binding cold-shock domain of the Chlamydomonas reinhardtii NAB1 protein and insights into RNA recognition

Biochemical Journal ◽

10.1042/bj20150217 ◽

2015 ◽

Vol 469 (1) ◽

pp. 97-106 ◽

Cited By ~ 4

Author(s):

Anne L. Sawyer ◽

Michael J. Landsberg ◽

Ian L. Ross ◽

Olaf Kruse ◽

Mehdi Mobli ◽

...

Keyword(s):

Chlamydomonas Reinhardtii ◽

Solution Structure ◽

Cold Shock ◽

Rna Binding ◽

Specific Binding ◽

Consensus Sequence ◽

Rna Recognition ◽

Nucleic Acid Binding ◽

Cold Shock Domain ◽

Higher Eukaryotes

We present the solution structure of the Chlamydomonas reinhardtii nucleic acid-binding protein 1 (NAB1) cold-shock domain (CSD) and compare this to homologues from bacteria and higher eukaryotes. Sequence-specific binding of the CSD consensus sequence (CSDCS) RNA element is also investigated.

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