UC Riverside researchers identify key cellular organelle involved in gene silencing

Conducting a recent study on plants, researchers at the University of California-Riverside have shown that repression of target gene expression occurs on the endoplasmic reticulum (ER), a cellular organelle that is an interconnected network of membranes— -- a finding they believe will expedite scientists’ understanding of the mechanism of gene silencing.

Amy Swinderman
RIVERSIDE, Calif.—Conducting a recent study on plants,researchers at the University of California-Riverside have shown thatrepression of target gene expression occurs on the endoplasmic reticulum (ER),a cellular organelle that is an interconnected network of membranes—a findingthey believe will expedite scientists' understanding of the mechanism of genesilencing.
In fact, the UC-Riverside study is the first to demonstratethat the ER is where miRNA-mediated translation repression occurs, according toDr. Xuemei Chen, lead researcher on an article published April 25 in thejournal Cell, and a professor ofplant cell and molecular biology at the university.
Translation inhibition is a major—but poorly understood—modeof action of microRNAs (miRNAs) in plants and animals. In particular, thesubcellular location where this process takes place is unknown, explains Chen.miRNA are known to regulate target genes by two major modes of action: theyeither destabilize the target RNAs, leading to their degradation, or they donot impact the stability of the target RNAs, but simply prevent them from beingtranslated into proteins—a process known as translation inhibition. The endresult of translation inhibition is that the genes do not get expressed. Justhow miRNAs cause translational inhibition of their target genes, however, isnot well understood.
"To understand how microRNAs repress target gene expression,we first need to know where microRNAs act in the cell," Chen says. "Until now,no one knew that membranes are essential for microRNA activity."
The researchers liken the ER to "flattened sacs andbranching tubules" that extend like a flat balloon throughout the cytoplasm inplant and animal cells. According to Chen, the ER has two types: rough andsmooth. Rough ER, which synthesizes and packages proteins, looks bumpy; smoothER, which acts in lipid synthesis and protein secretion, resembles tubes. TheER protein AMP1, she says, is anchored in the rough ER.
"My lab has been conducting research on AMP1 for manyyears," she says. "It's this protein that drew our attention to the ER. First,we realized that AMP1 is involved in miRNA-mediated translational inhibition.Then, since we already knew that AMP1 is localized in the rough ER, we shiftedour focus to this organelle."
The team observed that AMP1 encodes an integral membraneprotein associated with ER and ARGONAUTE1, the miRNA effector and a peripheral ERmembrane protein. Large differences in polysome association of miRNA targetRNAs are found between wild-type and the AMP1 mutant for membrane-bound, butnot total, polysomes. This, together with AMP1-independent recruitment of miRNAtarget transcripts to membrane fractions, shows that miRNAs inhibit thetranslation of target RNAs on the ER.
The study demonstrates that translation inhibition is animportant activity of plant miRNAs, reveals the subcellular location of thisactivity and uncovers a previously unknown function of the ER, says Chen.
"Our work shows that an integral membrane protein, AMP1, isrequired for the miRNA-mediated target gene repression to be successful. AsAMP1 has counterparts in animals, our findings in plants could have broader implications,"she says.
Next, Chen says her lab will attempt to crack the mechanismof miRNA-mediated translational inhibition. They will investigate, too, howmiRNAs are recruited to the ER.
"In this study, we uncover a role of AMP1 and LAMP1 inmiRNA-mediated translation inhibition, but not transcript cleavage," theresearchers concluded. "Given that plant miRNAs impact many aspects of plantdevelopment, it is not surprising that AMP1 alleles were isolated in a numberof genetic screens focusing on various aspects of plant development. The severedevelopmental defects of the AMP1 LAMP1 double mutant suggest that translationinhibition is an essential activity of plant miRNAs. However, it cannot beexcluded that AMP1 and LAMP1 possess miRNA-independent functions, and thesefunctions contribute to the pleiotropic developmental defects of the AMP1 LAMP1mutant." 
The study, "MicroRNAs Inhibit the Translation of TargetmRNAs on the Endoplasmic
Reticulum in Arabidopsis," was supported by grants from theU.S. National Institutes of Health, the National Science Foundation, the HowardHughes Medical Institute and the Gordon and Betty Moore Foundation.

Amy Swinderman

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