P-bodies

P-bodies were first described in the scientific literature by Bashkirov et al.{{cite journal | vauthors = Bashkirov VI, Scherthan H, Solinger JA, Buerstedde JM, Heyer WD | title = A mouse cytoplasmic exoribonuclease (mXRN1p) with preference for G4 tetraplex substrates | journal = The Journal of Cell Biology | volume = 136 | issue = 4 | pages = 761–773 | date = February 1997 | pmid = 9049243 | pmc = 2132493 | doi = 10.1083/jcb.136.4.761 }} 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.,{{cite journal | vauthors = Eystathioy T, Chan EK, Tenenbaum SA, Keene JD, Griffith K, Fritzler MJ | title = A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles | journal = Molecular Biology of the Cell | volume = 13 | issue = 4 | pages = 1338–1351 | date = April 2002 | pmid = 11950943 | pmc = 102273 | doi = 10.1091/mbc.01-11-0544 }}{{cite journal | vauthors = Ingelfinger D, Arndt-Jovin DJ, Lührmann R, Achsel T | title = The human LSm1-7 proteins colocalize with the mRNA-degrading enzymes Dcp1/2 and Xrnl in distinct cytoplasmic foci | journal = RNA | volume = 8 | issue = 12 | pages = 1489–1501 | date = December 2002 | pmid = 12515382 | pmc = 1370355 | doi = 10.1017/S1355838202021726 }}{{cite journal | vauthors = van Dijk E, Cougot N, Meyer S, Babajko S, Wahle E, Séraphin B | title = Human Dcp2: a catalytically active mRNA decapping enzyme located in specific cytoplasmic structures | journal = The EMBO Journal | volume = 21 | issue = 24 | pages = 6915–6924 | date = December 2002 | pmid = 12486012 | pmc = 139098 | doi = 10.1093/emboj/cdf678 }} 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. 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. Recently evidence has been presented suggesting that GW-bodies and P-bodies may in fact be different cellular components.{{cite journal | vauthors = Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O | title = Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity | journal = Nature Cell Biology | volume = 11 | issue = 9 | pages = 1143–1149 | date = September 2009 | pmid = 19684575 | doi = 10.1038/ncb1929 | s2cid = 205286867 }}{{Erratum|doi=10.1038/ncb1009-1272b|pmid=19684575|http://retractionwatch.com/2016/01/04/voinnets-notice-count-grows-notching-his-18th-correction/ Retraction Watch|http://retractionwatch.com/2016/01/26/swiss-funding-agency-cuts-off-voinnet-bans-him-for-3-years/ Retraction Watch|http://retractionwatch.com/page/2/?s=olivier+voinnet Retraction Watch|checked=yes}} 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. 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.{{cite journal | vauthors = Hoyle NP, Castelli LM, Campbell SG, Holmes LE, Ashe MP | title = Stress-dependent relocalization of translationally primed mRNPs to cytoplasmic granules that are kinetically and spatially distinct from P-bodies | journal = The Journal of Cell Biology | volume = 179 | issue = 1 | pages = 65–74 | date = October 2007 | pmid = 17908917 | pmc = 2064737 | doi = 10.1083/jcb.200707010 }}

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).{{cite journal | vauthors = Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R | title = MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies | journal = Nature Cell Biology | volume = 7 | issue = 7 | pages = 719–723 | date = July 2005 | pmid = 15937477 | pmc = 1855297 | doi = 10.1038/ncb1274 }}{{cite journal | vauthors = Liu J, Rivas FV, Wohlschlegel J, Yates JR, Parker R, Hannon GJ | title = A role for the P-body component GW182 in microRNA function | journal = Nature Cell Biology | volume = 7 | issue = 12 | pages = 1261–1266 | date = December 2005 | pmid = 16284623 | pmc = 1804202 | doi = 10.1038/ncb1333 }}{{cite journal | vauthors = Sen GL, Blau HM | title = Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies | journal = Nature Cell Biology | volume = 7 | issue = 6 | pages = 633–636 | date = June 2005 | pmid = 15908945 | doi = 10.1038/ncb1265 | s2cid = 6085169 }}{{cite journal | vauthors = Eystathioy T, Jakymiw A, Chan EK, Séraphin B, Cougot N, Fritzler MJ | title = The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies | journal = RNA | volume = 9 | issue = 10 | pages = 1171–1173 | date = October 2003 | pmid = 13130130 | pmc = 1370480 | doi = 10.1261/rna.5810203 }} 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.

In 2017, a new method to purify processing bodies was published. 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. 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.

In 2018, Youn et al. took a proximity labeling approach called BioID to identify and predict the processing body proteome.{{cite journal | vauthors = Youn JY, Dunham WH, Hong SJ, Knight JD, Bashkurov M, Chen GI, Bagci H, Rathod B, MacLeod G, Eng SW, Angers S, Morris Q, Fabian M, Côté JF, Gingras AC | display-authors = 6 | title = High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies | journal = Molecular Cell | volume = 69 | issue = 3 | pages = 517–532.e11 | date = February 2018 | pmid = 29395067 | doi = 10.1016/j.molcel.2017.12.020 | doi-access = free }} 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.

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• {{cite journal | vauthors = Kulkarni M, Ozgur S, Stoecklin G | title = On track with P-bodies | journal = Biochemical Society Transactions | volume = 38 | issue = Pt 1 | pages = 242–251 | date = February 2010 | pmid = 20074068 | doi = 10.1042/BST0380242 }}
• {{cite journal | vauthors = Eulalio A, Behm-Ansmant I, Izaurralde E | title = P bodies: at the crossroads of post-transcriptional pathways | journal = Nature Reviews. Molecular Cell Biology | volume = 8 | issue = 1 | pages = 9–22 | date = January 2007 | pmid = 17183357 | doi = 10.1038/nrm2080 | s2cid = 41419388 }}
• {{cite journal | vauthors = Marx J | title = Molecular biology. P-bodies mark the spot for controlling protein production | journal = Science | volume = 310 | issue = 5749 | pages = 764–765 | date = November 2005 | pmid = 16272094 | doi = 10.1126/science.310.5749.764 | s2cid = 11106208 }}
• {{cite journal | vauthors = Anderson P, Kedersha N | title = RNA granules: post-transcriptional and epigenetic modulators of gene expression | journal = Nature Reviews. Molecular Cell Biology | volume = 10 | issue = 6 | pages = 430–436 | date = June 2009 | pmid = 19461665 | doi = 10.1038/nrm2694 | s2cid = 26578027 }}

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Category:Molecular biology

Category:Biochemistry