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P-bodies

Not to be confused with P element.
"P-body" redirects here. For the fictional robot, see Portal 2.

In cellular biology, P-bodies, or processing bodies, are distinct foci formed by phase separation within the cytoplasm of a eukaryotic cell consisting of many enzymes involved in mRNA turnover.[1] P-bodies are highly conserved structures and have been observed in somatic cells originating from vertebrates and invertebrates, plants and yeast. To date, P-bodies have been demonstrated to play fundamental roles in general mRNA decay, nonsense-mediated mRNA decay, adenylate-uridylate-rich element mediated mRNA decay, and microRNA (miRNA) induced mRNA silencing.[2] Not all mRNAs which enter P-bodies are degraded, as it has been demonstrated that some mRNAs can exit P-bodies and re-initiate translation.[3][4] Purification and sequencing of the mRNA from purified processing bodies showed that these mRNAs are largely translationally repressed upstream of translation initiation and are protected from 5' mRNA decay.[5]

P-bodies were originally proposed to be the sites of mRNA degradation in the cell and involved in decapping and digestion of mRNAs earmarked for destruction.[6][7] Later work called this into question suggesting P bodies store mRNA until needed for translation.[8][5][9]

In neurons, P-bodies are moved by motor proteins in response to stimulation. This is likely tied to local translation in dendrites.[10]

History

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P-bodies were first described in the scientific literature by Bashkirov et al.[11] in 1997, in which they describe "small granules… discrete, prominent foci" as the cytoplasmic location of the mouse exoribonuclease mXrn1p. It wasn’t until 2002 that a glimpse into the nature and importance of these cytoplasmic foci was published.,[12][13][14] when researchers demonstrated that multiple proteins involved with mRNA degradation localize to the foci. Their importance was recognized after experimental evidence was obtained pointing to P-bodies as the sites of mRNA degradation in the cell.[7] The researchers named these structures processing bodies or "P bodies". During this time, many descriptive names were used also to identify the processing bodies, including "GW-bodies" and "decapping-bodies"; however "P-bodies" was the term chosen and is now widely used and accepted in the scientific literature.[7] Recently evidence has been presented suggesting that GW-bodies and P-bodies may in fact be different cellular components.[15] The evidence being that GW182 and Ago2, both associated with miRNA gene silencing, are found exclusively in multivesicular bodies or GW-bodies and are not localized to P-bodies. Also of note, P-bodies are not equivalent to stress granules and they contain largely non-overlapping proteins.[5] The two structures support overlapping cellular functions but generally occur under different stimuli. Hoyle et al. suggests a novel site termed EGP bodies, or stress granules, may be responsible for mRNA storage as these sites lack the decapping enzyme.[16]

Associations with microRNA

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microRNA mediated repression occurs in two ways, either by translational repression or stimulating mRNA decay. miRNA recruit the RISC complex to the mRNA to which they are bound. The link to P-bodies comes by the fact that many, if not most, of the proteins necessary for miRNA gene silencing are localized to P-bodies, as reviewed by Kulkarni et al. (2010).[2][17][18][19][20] These proteins include, but are not limited to, the scaffold protein GW182, Argonaute (Ago), decapping enzymes and RNA helicases. The current evidence points toward P-bodies as being scaffolding centers of miRNA function, especially due to the evidence that a knock down of GW182 disrupts P-body formation. However, there remain many unanswered questions about P-bodies and their relationship to miRNA activity. Specifically, it is unknown whether there is a context dependent (stress state versus normal) specificity to the P-body's mechanism of action. Based on the evidence that P-bodies sometimes are the site of mRNA decay and sometimes the mRNA can exit the P-bodies and re-initiate translation, the question remains of what controls this switch. Another ambiguous point to be addressed is whether the proteins that localize to P-bodies are actively functioning in the miRNA gene silencing process or whether they are merely on standby.

Protein composition

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In 2017, a new method to purify processing bodies was published.[5] Hubstenberger et al. used fluorescence-activated particle sorting (a method based on the ideas of fluorescence-activated cell sorting) to purify processing bodies from human epithelial cells. From these purified processing bodies they were able to use mass spectrometry and RNA sequencing to determine which proteins and RNAs are found in processing bodies, respectively. This study identified 125 proteins that are significantly associated with processing bodies.[5] Notably this work provided the most compelling evidence up to this date that P-bodies might not be the sites of degradation in the cell and instead used for storage of translationally repressed mRNA. This observation was further supported by single molecule imaging of mRNA by the Chao group in 2017.[9]

In 2018, Youn et al. took a proximity labeling approach called BioID to identify and predict the processing body proteome.[21] They engineered cells to express several processing body-localized proteins as fusion proteins with the BirA* enzyme. When the cells are incubated with biotin, BirA* will biotinylate proteins that are nearby, thus tagging the proteins within processing bodies with a biotin tag. Streptavidin was then used to isolate the tagged proteins and mass spectrometry to identify them. Using this approach, Youn et al. identified 42 proteins that localize to processing bodies.[21]

Gene ID Protein References Also found in stress granules?
MOV10 MOV10 [5][21] Yes
EDC3 EDC3 [21] Yes
EDC4 EDC4 [5] Yes
ZCCHC11 TUT4 [5] No
DHX9 DHX9 [5] No
RPS27A RS27A [5] No
UPF1 RENT1 [5] Yes
ZCCHC3 ZCHC3 [5] No
SMARCA5 SMCA5 [5] No
TOP2A TOP2A [5] No
HSPA2 HSP72 [5] No
SPTAN1 SPTN1 [5] No
SMC1A SMC1A [5] No
ACTBL2 ACTBL [5] Yes
SPTBN1 SPTB2 [5] No
DHX15 DHX15 [5] No
ARG1 ARGI1 [5] No
TOP2B TOP2B [5] No
APOBEC3F ABC3F [5] No
NOP58 NOP58 [5] Yes
RPF2 RPF2 [5] No
S100A9 S100A9 [5] Yes
DDX41 DDX41 [5] No
KIF23 KIF23 [5] Yes
AZGP1 ZA2G [5] No
DDX50 DDX50 [5] Yes
SERPINB3 SPB3 [5] No
SBSN SBSN [5] No
BAZ1B BAZ1B [5] No
MYO1C MYO1C [5] No
EIF4A3 IF4A3 [5] No
SERPINB12 SPB12 [5] No
EFTUD2 U5S1 [5] No
RBM15B RB15B [5] No
AGO2 AGO2 [5] Yes
MYH10 MYH10 [5] No
DDX10 DDX10 [5] No
FABP5 FABP5 [5] No
SLC25A5 ADT2 [5] No
DMKN DMKN [5] No
DCP2 DCP2 [5][13][14][22] No
S100A8 S10A8 [5] No
NCBP1 NCBP1 [5] No
YTHDC2 YTDC2 [5] No
NOL6 NOL6 [5] No
XAB2 SYF1 [5] No
PUF60 PUF60 [5] No
RBM19 RBM19 [5] No
WDR33 WDR33 [5] No
PNRC1 PNRC1 [5] No
SLC25A6 ADT3 [5] No
MCM7 MCM7 [5] Yes
GSDMA GSDMA [5] No
HSPB1 HSPB1 [5] Yes
LYZ LYSC [5] No
DHX30 DHX30 [5] Yes
BRIX1 BRX1 [5] No
MEX3A MEX3A [5] Yes
MSI1 MSI1H [5] Yes
RBM25 RBM25 [5] No
UTP11L UTP11 [5] No
UTP15 UTP15 [5] No
SMG7 SMG7 [5][21] Yes
AGO1 AGO1 [5] Yes
LGALS7 LEG7 [5] No
MYO1D MYO1D [5] No
XRCC5 XRCC5 [5] No
DDX6 DDX6/p54/RCK [5][21][23][24] Yes
ZC3HAV1 ZCCHV [5] Yes
DDX27 DDX27 [5] No
NUMA1 NUMA1 [5] No
DSG1 DSG1 [5] No
NOP56 NOP56 [5] No
LSM14B LS14B [5] Yes
EIF4E2 EIF4E2 [21] Yes
EIF4ENIF1 4ET [5][21] Yes
LSM14A LS14A [5][21] Yes
IGF2BP2 IF2B2 [5] Yes
DDX21 DDX21 [5] Yes
DSC1 DSC1 [5] No
NKRF NKRF [5] No
DCP1B DCP1B [5][24] No
SMC3 SMC3 [5] No
RPS3 RS3 [5] Yes
PUM1 PUM1 [5] Yes
PIP PIP [5] No
RPL26 RL26 [5] No
GTPBP4 NOG1 [5] No
PES1 PESC [5] No
DCP1A DCP1A [5][13][14][22][20] No
ELAVL2 ELAV2 [5] Yes
IGLC2 LAC2 [5] No
IGF2BP1 IF2B1 [5] Yes
RPS16 RS16 [5] No
HNRNPU HNRPU [5] No
IGF2BP3 IF2B3 [5] Yes
SF3B1 SF3B1 [5] No
STAU2 STAU2 [5] Yes
ZFR ZFR [5] No
HNRNPM HNRPM [5] No
ELAVL1 ELAV1 [5] Yes
FAM120A F120A [5] Yes
STRBP STRBP [5] No
RBM15 RBM15 [5] No
LMNB2 LMNB2 [5] No
NIFK MK67I [5] No
TF TRFE [5] No
HNRNPR HNRPR [5] No
LMNB1 LMNB1 [5] No
ILF2 ILF2 [5] No
H2AFY H2AY [5] No
RBM28 RBM28 [5] No
MATR3 MATR3 [5] No
SYNCRIP HNRPQ [5] Yes
HNRNPCL1 HNRCL [5] No
APOA1 APOA1 [5] No
XRCC6 XRCC6 [5] No
RPS4X RS4X [5] No
DDX18 DDX18 [5] No
ILF3 ILF3 [5] Yes
SAFB2 SAFB2 [5] Yes
RBMX RBMX [5] No
ATAD3A ATD3A [5] Yes
HNRNPC HNRPC [5] No
RBMXL1 RMXL1 [5] No
IMMT IMMT [5] No
ALB ALBU [5] No
CSNK1D CK1𝛿 [23] No
XRN1 XRN1 [11][13][21][22] Yes
TNRC6A GW182 [21][22][12][20][25] Yes
TNRC6B TNRC6B [21] Yes
TNRC6C TNRC6C [21] Yes
LSM4 LSM4 [20][13] No
LSM1 LSM1 [13] No
LSM2 LSM2 [13] No
LSM3 LSM3 [13][24] Yes
LSM5 LSM5 [13] No
LSM6 LSM6 [13] No
LSM7 LSM7 [13] No
CNOT1 CCR4/CNOT1 [24][21] Yes
CNOT10 CNOT10 [21] Yes
CNOT11 CNOT11 [21] Yes
CNOT2 CNOT2 [21] Yes
CNOT3 CNOT3 [21] Yes
CNOT4 CNOT4 [21] Yes
CNOT6 CNOT6 [21] Yes
CNOT6L CNOT6L [21] Yes
CNOT7 CNOT7 [21] Yes
CNOT8 CNOT8 [21] Yes
CNOT9 CNOT9 [21] No
RBFOX1 RBFOX1 [26] Yes
ANKHD1 ANKHD1 [21] Yes
ANKRD17 ANKRD17 [21] Yes
BTG3 BTG3 [21] Yes
CEP192 CEP192 [21] No
CPEB4 CPEB4 [21] Yes
CPVL CPVL [21] Yes
DIS3L DIS3L [21] No
DVL3 DVL3 [21] No
FAM193A FAM193A [21] No
GIGYF2 GIGYF2 [21] Yes
HELZ HELZ [21] Yes
KIAA0232 KIAA0232 [21] Yes
KIAA0355 KIAA0355 [21] No
MARF1 MARF1 [21] Yes
N4BP2 N4BP2 [21] No
PATL1 PATL1 [21] Yes
RNF219 RNF219 [21] Yes
ST7 ST7 [21] Yes
TMEM131 TMEM131 [21] Yes
TNKS1BP1 TNKS1BP1 [21] Yes
TTC17 TTC17 [21] Yes

References

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  24. ^ a b c d Cougot N, Babajko S, Séraphin B (April 2004). "Cytoplasmic foci are sites of mRNA decay in human cells". The Journal of Cell Biology. 165 (1): 31–40. doi:10.1083/jcb.200309008. PMC 2172085. PMID 15067023.
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Further reading

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