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Chapter 25 : Sponges and Predators in the Small RNA World
Authors:
Nara Figueroa-Bossi1,
Lionello Bossi2
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Affiliations:
1: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University of Paris-Sud, University of Paris-Saclay, Gif-sur-Yvette, France;
2: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University of Paris-Sud, University of Paris-Saclay, Gif-sur-Yvette, France
Content Type: Monograph
Publication Year:
2019
Category: Microbial Genetics and Molecular Biology
Book DOI:
10.1128/9781683670247
Chapter DOI:
10.1128/microbiolspec.RWR-0021-2018
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Abstract:
MicroRNAs (miRNAs) are 20- to-24-nucleotide (nt)-long RNAs that guide Argonaute proteins to silence mRNA expression in animal and plant cells ( 1 – 3 ). Similarly to bacterial trans-encoded small RNAs (sRNAs), miRNAs act by establishing imperfect base-pair interactions with seed sequences that can be as short as 6 to 8 nt. Seeking ways to selectively control miRNA activity in vivo, a decade ago Ebert and coworkers engineered transcripts containing multiple tandemly arranged target sites for one or more miRNAs and had these constructs expressed at high levels in transfected mammalian cells ( 4 ). They found the exogenous RNAs to have the ability to sequester (“soak up”) the miRNAs, relieving the regulation of their natural targets. The authors termed the artificial transcripts “microRNA sponges.” At about the same time, a study on the mechanism responsible for inhibiting the activity of a miRNA (miR399) in plant cells identified an endogenous noncoding RNA, named IPS1, that could base-pair with miR399 and compete for its binding to the primary target ( 5 ). This indicated that a natural RNA could have sponge-like activity and that target site amplification was not required for this effect. Following these initial findings, several examples of miRNA target mimicry have been described involving different types of coding and noncoding RNAs ( 6 , 7 ), including some of viral origin ( 8 , 9 ). Particularly noteworthy is the case of the circular antisense RNA named CDR1as, highly expressed in human and mouse brain, which harbors as many as 74 potential target sites for the miR-7 miRNA and thus closely fulfills the original definition of a sponge ( 10 ). Recent evidence showed CDR1as to be a highly efficient miR-7 sponge in vivo: in cells lacking CDR1as, deregulation of miR-7 networks leads to profound defects in brain development and function ( 11 ).
Citation:
Figueroa-Bossi N, Bossi L.
2019.
Sponges and Predators in the Small RNA World,
p 441-451.
In
Storz G, Papenfort K (ed),
Regulating with RNA in Bacteria and Archaea.
ASM Press, Washington, DC.
doi: 10.1128/microbiolspec.RWR-0021-2018
Figures
Sponges and Predators in the Small RNA World
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Citation:
Figueroa-Bossi N, Bossi L.
2019.
Sponges and Predators in the Small RNA World,
p 441-451.
In
Storz G, Papenfort K (ed),
Regulating with RNA in Bacteria and Archaea.
ASM Press, Washington, DC.
doi: 10.1128/microbiolspec.RWR-0021-2018
/content/10.1128/9781683670247.chap25.fig25-1
Figure 1
Regulation of chitosugar uptake in Salmonella and E. coli. The chiP gene and the chbBCARFG operon encode proteins involved in the uptake and utilization of chitin-derived sugars. When no chitosugars are available, ChiP synthesis is prevented by constitutively made ChiX sRNA, which represses translation of chiP mRNA (made at a relatively high basal level), while the chbBCARF operon is repressed transcriptionally by the NagC repressor (not shown). ChiX further lowers the uninduced levels of the chb mRNA by pairing with a sequence in the chbB-chbC intercistronic region. In the presence of chitosugars, transcriptional activation of chbBCARF operon produces a large accumulation of the polycistronic mRNA. Now in excess over ChiX, this mRNA titrates out ChiX through base-pairing and promotes its degradation. ChiX depletion results in the derepression of the chiP mRNA.
10.1128/9781683670247/fig25-1_thmb.gif
10.1128/9781683670247/fig25-1.gif
Figure 1
Regulation of chitosugar uptake in Salmonella and E. coli. The chiP gene and the chbBCARFG operon encode proteins involved in the uptake and utilization of chitin-derived sugars. When no chitosugars are available, ChiP synthesis is prevented by constitutively made ChiX sRNA, which represses translation of chiP mRNA (made at a relatively high basal level), while the chbBCARF operon is repressed transcriptionally by the NagC repressor (not shown). ChiX further lowers the uninduced levels of the chb mRNA by pairing with a sequence in the chbB-chbC intercistronic region. In the presence of chitosugars, transcriptional activation of chbBCARF operon produces a large accumulation of the polycistronic mRNA. Now in excess over ChiX, this mRNA titrates out ChiX through base-pairing and promotes its degradation. ChiX depletion results in the derepression of the chiP mRNA.
Citation:
Figueroa-Bossi N, Bossi L.
2019.
Sponges and Predators in the Small RNA World,
p 441-451.
In
Storz G, Papenfort K (ed),
Regulating with RNA in Bacteria and Archaea.
ASM Press, Washington, DC.
doi: 10.1128/microbiolspec.RWR-0021-2018
/content/10.1128/9781683670247.chap25.fig25-2
Figure 2
sRNA sponging by a tRNA spacer sequence. The sRNAs RybB (blue) and RyhB (purple) are made in response to envelope stress or iron limitation, respectively. An ∼50-nt RNA, named 3′ETS
leuZ
(red), released by RNase E cleavage of the glyW-cysT-leuZ tRNA precursor (top) can form stable base-pair interactions with both RybB and RyhB. This allows 3′ETS
leuZ
to capture and sequester RybB and RyhB molecules that are made adventitiously (in the absence of any stress) due to transcriptional noise (left). Under inducing conditions (envelope stress or iron limitation), accumulation of either RybB or RyhB saturates the sponging capacity of 3′ETS
leuZ
. This sets the threshold concentration (dotted line) that either of the two sRNAs must attain to begin performing its regulatory task: downregulation of OMPs for RybB (middle) or of nonessential iron-binding proteins for RyhB (right).
10.1128/9781683670247/fig25-2_thmb.gif
10.1128/9781683670247/fig25-2.gif
Figure 2
sRNA sponging by a tRNA spacer sequence. The sRNAs RybB (blue) and RyhB (purple) are made in response to envelope stress or iron limitation, respectively. An ∼50-nt RNA, named 3′ETS leuZ (red), released by RNase E cleavage of the glyW-cysT-leuZ tRNA precursor (top) can form stable base-pair interactions with both RybB and RyhB. This allows 3′ETS leuZ to capture and sequester RybB and RyhB molecules that are made adventitiously (in the absence of any stress) due to transcriptional noise (left). Under inducing conditions (envelope stress or iron limitation), accumulation of either RybB or RyhB saturates the sponging capacity of 3′ETS leuZ . This sets the threshold concentration (dotted line) that either of the two sRNAs must attain to begin performing its regulatory task: downregulation of OMPs for RybB (middle) or of nonessential iron-binding proteins for RyhB (right).
Citation:
Figueroa-Bossi N, Bossi L.
2019.
Sponges and Predators in the Small RNA World,
p 441-451.
In
Storz G, Papenfort K (ed),
Regulating with RNA in Bacteria and Archaea.
ASM Press, Washington, DC.
doi: 10.1128/microbiolspec.RWR-0021-2018
/content/10.1128/9781683670247.chap25.fig25-3
Figure 3
Target-mediated derepression of the GcvB regulon. The sRNA GcvB downregulates several mRNAs encoding amino acid and small peptide transporters. Among these is the gltIJKL mRNA (left). Presence of a leaky Rho-independent transcription terminator in the spacer between gltI and gltJ causes a fraction of transcripts initiating at the gltI promoter to terminate prematurely in the spacer region (right). RNase E cleavage of the prematurely terminated transcripts generates SroC, an ∼150-nt RNA, which captures GcvB through a base-pairing interaction and destabilizes it. As a result, all of the GcvB targets become derepressed. Since the SroC precursor RNA itself is one of these targets, SroC activity drives a feedforward regulatory loop.
10.1128/9781683670247/fig25-3_thmb.gif
10.1128/9781683670247/fig25-3.gif
Figure 3
Target-mediated derepression of the GcvB regulon. The sRNA GcvB downregulates several mRNAs encoding amino acid and small peptide transporters. Among these is the gltIJKL mRNA (left). Presence of a leaky Rho-independent transcription terminator in the spacer between gltI and gltJ causes a fraction of transcripts initiating at the gltI promoter to terminate prematurely in the spacer region (right). RNase E cleavage of the prematurely terminated transcripts generates SroC, an ∼150-nt RNA, which captures GcvB through a base-pairing interaction and destabilizes it. As a result, all of the GcvB targets become derepressed. Since the SroC precursor RNA itself is one of these targets, SroC activity drives a feedforward regulatory loop.
Citation:
Figueroa-Bossi N, Bossi L.
2019.
Sponges and Predators in the Small RNA World,
p 441-451.
In
Storz G, Papenfort K (ed),
Regulating with RNA in Bacteria and Archaea.
ASM Press, Washington, DC.
doi: 10.1128/microbiolspec.RWR-0021-2018
/content/10.1128/9781683670247.chap25.fig25-4
Figure 4
A sponging relay model. Depicted are two hypothetical sRNA networks (A and B) linked by an mRNA node (cyan-filled circle). (Top) The two sRNAs downregulate their respective targets. (Bottom) A transcriptional regulatory event leads to a large increase in the concentration of one of the mRNAs in network A (yellow-filled circle). The accumulated mRNA sequesters and destabilizes its cognate sRNA, resulting in the derepression of the entire network A, including the nodal mRNA. In turn, the latter acts as a sponge for cognate sRNA in network B, thus relieving, or attenuating (depicted here), the repression of the B network.
10.1128/9781683670247/fig25-4_thmb.gif
10.1128/9781683670247/fig25-4.gif
Figure 4
A sponging relay model. Depicted are two hypothetical sRNA networks (A and B) linked by an mRNA node (cyan-filled circle). (Top) The two sRNAs downregulate their respective targets. (Bottom) A transcriptional regulatory event leads to a large increase in the concentration of one of the mRNAs in network A (yellow-filled circle). The accumulated mRNA sequesters and destabilizes its cognate sRNA, resulting in the derepression of the entire network A, including the nodal mRNA. In turn, the latter acts as a sponge for cognate sRNA in network B, thus relieving, or attenuating (depicted here), the repression of the B network.
Citation:
Figueroa-Bossi N, Bossi L.
2019.
Sponges and Predators in the Small RNA World,
p 441-451.
In
Storz G, Papenfort K (ed),
Regulating with RNA in Bacteria and Archaea.
ASM Press, Washington, DC.
doi: 10.1128/microbiolspec.RWR-0021-2018
References
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