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Review
. 2015;35(5):379-400.
doi: 10.1615/critrevimmunol.v35.i5.30.

Regulatory Roles of Rpl22 in Hematopoiesis: An Old Dog with New Tricks

Shawn P Fahl  1 , Minshi Wang  1 , Yong Zhang  1 , Anne-Cecile E Duc  1 , David L Wiest  1
Affiliations
Review

Regulatory Roles of Rpl22 in Hematopoiesis: An Old Dog with New Tricks

Shawn P Fahl et al. Crit Rev Immunol. 2015.

Abstract

Ribosomal proteins have long been known to serve critical roles in facilitating the biogenesis of the ribosome and its ability to synthesize proteins. However, evidence is emerging that suggests ribosomal proteins are also capable of performing tissue-restricted, regulatory functions that impact normal development and pathological conditions, including cancer. The challenge in studying such regulatory functions is that elimination of many ribosomal proteins also disrupts ribosome biogenesis and/or function. Thus, it is difficult to determine whether developmental abnormalities resulting from ablation of a ribosomal protein result from loss of core ribosome functions or from loss of the regulatory function of the ribosomal protein. Rpl22, a ribosomal protein component of the large 60S subunit, provides insight into this conundrum; Rpl22 is dispensable for both ribosome biogenesis and protein synthesis yet its ablation causes tissue-restricted disruptions in development. Here we review evidence supporting the regulatory functions of Rpl22 and other ribosomal proteins.

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Figures

Figure 1
Figure 1. Rpl22 and its location in the ribosome
A) The position of Rpl22 in the published 80S ribosome model. Red: small 40S subunit, Green: large 60S subunit, Blue: Rpl22. B) Amino acid sequence of murine Rpl22. The RNA-binding helices (Red) and nuclear localization signal (NLS; blue) are indicated. C) Cryo-EM depiction of Rpl22 interacting with 28S rRNA. D) Ribbon diagram of Rpl22 secondary structure as it interacts with 28S rRNA. The red arrow indicates the RNA-binding helices.
Figure 2
Figure 2. Functional interplay between Rpl22 and its highly homologous paralog, Rpl22l1
A) RNA consensus hairpin/motif bound by Rpl22 (adapted from Dobbelstein and Shenk, J Virology, 1995). B) Evolutionary conservation of the RNA-binding domains of Rpl22 and Rpl22l1. C) Rpl22 and Rpl22l1 play distinct, and opposing roles in HSC emergence. Rpl22 and Rpl22l1 both bind to Smad1 mRNA and control its translation, with Rpl22 playing a repressive role and Rpl22l1 acting to oppose that repression. D) HSC emergence is controlled by the opposing actions of Rpl22 and Rpl22l1 on Smad1 expression. When Rpl22 and Rpl22l1 are in balance, HSC emergence occurs normally; however, if Rpl22 dominates, it represses Smad1, blocks HSC emergence and causes anemia, whereas if Rpl22l1 dominates, HSC emergence is uncontrolled, leading to an increased predisposition to transformation.
Figure 3
Figure 3. Rpl22 and Rpl22l1 have multiple roles during hematopoiesis
Rpl22 and Rpl22l1 have opposing effects on the translation of Smad1 mRNA, and the balance of their antagonistic activities control HSC emergence by controlling the expression of Smad1. Rpl22 also controls key developmental checkpoints during B and T cell development by controlling p53 expression in a lineage-restricted manner.
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