Sjögren Syndrome Antigen B (SSB)/La Promotes Global MicroRNA Expression by Binding MicroRNA Precursors through Stem-Loop Recognition

Abstract

Background: MicroRNA biogenesis is a multistep process regulated by RNA-binding proteins. Results: Sjögren syndrome antigen B (SSB)/La binds stem-loop precursor microRNAs (pre-miRNA) and is required for microRNA expression. Conclusion: La/SSB promotes global microRNA expression by stabilizing pre-miRNAs from nuclease-mediated decay. Significance: This study reveals a novel concept of pre-miRNA holding complex that protects and escorts pre-miRNAs in microRNA biogenesis pathway.

Targeted Deletion of the Gene Encoding the La Autoantigen (Sjögren's Syndrome Antigen B) in B Cells or the Frontal Brain Causes Extensive Tissue Loss

“…As noted in the introduction, mammalian La has been implicated in the regulation of multiple mRNAs, including those for housekeeping functions, such as ribosomal proteins. In addition, La has been implicated in the biogenesis of rRNA and microRNAs (miRNAs) (59)(60)(61). Thus, although we have demonstrated altered pre-tRNA metabolism in the La knockout brain, present technology does not allow us to determine if deficiency in this pathway alone is sufficient to cause cell lethality and the other phenotypes observed.…”

“…Such a function may involve an activity in addition to the binding and protection of pre-tRNAs and/or other RNA polymerase III transcripts that localizes to RRM2. RNA chaperone and other activities that appear to rely on RNA binding distinguishable from UUU-3=-OH binding may be involved (31,62), affecting mRNA translation, as noted above, or an miRNA-related function (60,61). Alternatively, an additional RRM may allow more control or regulation over the pre-RNA or other polymerase III transcript binding activity, perhaps related to the pre-tRNA chaperone activity of RRM1 (17,63).…”

The Lupus Autoantigen La Prevents Mis-channeling of tRNA Fragments into the Human MicroRNA Pathway

“…La has been implicated in RISC activity in Drosophila (Liu et al, 2011), as well as global miRNA-processing (Liang et al, 2013).…”

The RNA chaperon activity of the human La protein (LARP3)

“…The finding that the RNA chaperone activity of La is required to stimulate both IRES-as well as cap-dependent translation raises the question about the location and the nature of RNA elements/structures recognized by La. It is possible that the chaperone activity of La has an indirect effect on translation by contributing to the processing of RNA molecules required for protein synthesis such as pre-tRNAs [6,7,45] or due to effects on microRNA processing [9,10] . However, 35 S-metabolic-labeling and 2D gel electrophoresis analysis does not suggest that La depletion has a global effect on protein synthesis in HeLa cells [17] .…”

“…La interacts with the precursors of a variety of different RNA molecules e.g. tRNAs, mircoRNAs, snoRNAs [6][7][8] [ [9][10][11] and binds to long viral and cellular mRNAs. Besides its LAM:RRM1-mediated interaction with the oligo(U) 3'-termini common to nascent RNA polymerase III transcripts such as pre-tRNAs [12] , human La can bind to the 5'-terminus of mRNAs referred to as terminal polypyrimidine tract (TOP) mRNAs [13][14][15] , and internal RNA elements in RNAs such as MDM2 [16] , cyclin D1 [17] , XIAP [18] , human immunodeficiency virus [19] , hepatitis C [20] and A virus [21] and polio virus [22] .…”