Mechanisms and Control of Protein Translation in the Kidney

Abstract

Translational control of protein synthesis is critical for cell division, homeostasis and survival. Recent data indicate that dysregulation of protein synthesis that leads to either increased or decreased expression of specific proteins contributes to the manifestations of various kidney diseases. Most of the control of protein synthesis occurs in the first or initiation phase, which is also the most complicated. Following the initiation phase is the elongation phase where the peptide chain is formed. RNA transcripts are released from ribosomes after the termination phase. Transcripts can be translated in a cap-dependent or cap-independent manner. The mTOR (mammalian target of rapamycin) cascade regulates translation of most cap-dependent transcripts at the level of initiation and elongation, which represents 95% of total transcripts. During specific events (e.g. mitosis, stress cell survival) control of the less-common cap-independent transcripts occurs which allows the cell to adapt to the new state. Activation of stress kinases and inactivation of the mTOR pathway are at the center of this adaptive mechanism. Recent studies have elucidated the role of micro-RNAs (miRs) in controlling translation. miRs bind directly to specific transcripts and most often directly reduce translation; however, by targeting other positive or negative regulators of the pathways regulating protein synthesis they may indirectly affect synthetic levels of other transcripts. Several examples are described below in which these mechanisms are intertwined and act together to dysregulate protein synthesis in the diseased kidney.

Activation of Sirt1 by Resveratrol Inhibits TNF-α Induced Inflammation in Fibroblasts

“…Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase which regulates protein synthesis [69], [70]. Studies report that activation of mTOR plays a role in TNF-α-induced inflammatory cascades [71], and is also implicated in inflammation related diseases [72].…”

Role of the mTOR Pathway in LPS-Activated Monocytes: Influence of Hypertonic Saline

“…Nutrients such as amino acids, growth factors (such as insulin) or the energy status of the cell can activate the cascade, which lead, among others, to the phosphorylation and inhibition of the translational inhibitor 4E-BP1, and the release of the cap-binding factor eIF4E. The dysregulation of the mTOR cascade has been implicated in numerous processes and disorders, ranging from cancers to metabolic disorders to aging (12). Several lines of evidence suggest that translational control through the mTOR checkpoint could be involved in the regulation of the innate immune inflammatory response (24, 25).…”

“…Activated Akt is able to phosphorylate mTOR at Ser2448 (47). Targets of mTOR include the p70 S6 kinase (p70S6K) and the translational repressor 4E-BP1 (reviewed in (12, 13)). LY294002 is an inhibitor of the PI3K kinase and rapamycin is a specific inhibitor of the mTOR kinase.…”

“…The TOR pathway is conserved from yeast to mammals and has been shown to control cell growth, cell cycle, neurite plasticity and metabolism, in addition to translation initiation (10). At the same time, dysregulation of the mTOR pathway has been implicated in many disorders, such as tumorigenesis, metastasis (11), metabolic diseases (12, 13), cardiac hypertrophy (14), sepsis (15, 16) and more recently after traumatic brain injury (17). As activation of mTOR has been shown to facilitate translation initiation, the rate-limiting step in protein synthesis, we hypothesized that the mTOR pathway, which control the cap-dependent translation initiation phase, was activated by lipopolysaccharide (LPS) and responsible for cytokine production.…”

MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation

“…In recent years, the importance of posttranscriptional regulation of inflammation by microRNAs (miRs) has become increasingly apparent (28). Mature miRs are short noncoding RNAs that bind to (partially) complementary sequences, most commonly found in the 3=UTR (untranslated region) of target mRNAs, which results in inhibition of protein synthesis by degradation or translational repression of the target mRNA.…”