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Taking a Step Back from Back-Translocation: an Integrative View of LepA/EF4's Cellular Function.

ABSTRACT: Protein synthesis, the translation of mRNA into a polypeptide facilitated by the ribosome, is assisted by a variety of protein factors, some of which are GTPases. In addition to four highly conserved and well-understood GTPases with known function, there are also a number of noncanonical GTPases that are implicated in translation but whose functions are not fully understood. LepA/EF4 is one of these noncanonical GTPases. It is highly conserved and present in bacteria, mitochondria, and chloroplasts, but its functional role in the cell remains unknown. LepA's sequence and domain arrangement are very similar to those of other translational GTPases, but it contains a unique C-terminal domain (CTD) that is likely essential to its specific function in the cell. Three main hypotheses about the function of LepA have been brought forward to date: (i) LepA is a back-translocase, (ii) LepA relieves ribosome stalling or facilitates sequestration, and (iii) LepA is involved in ribosome biogenesis. This review examines the structural and biochemical information available on bacterial LepA and discusses it on the background of the available in vivo information from higher organisms in order to broaden the view regarding LepA's functional role in the cell and how the structure of its unique CTD might be involved in facilitating this role.

SUBMITTER: Heller JLE

PROVIDER: S-EPMC5452718 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Taking a Step Back from Back-Translocation: an Integrative View of LepA/EF4's Cellular Function.

Heller Jalyce L E JLE Kamalampeta Rajashekhar R Wieden Hans-Joachim HJ

Molecular and cellular biology 20170531 12

Protein synthesis, the translation of mRNA into a polypeptide facilitated by the ribosome, is assisted by a variety of protein factors, some of which are GTPases. In addition to four highly conserved and well-understood GTPases with known function, there are also a number of noncanonical GTPases that are implicated in translation but whose functions are not fully understood. LepA/EF4 is one of these noncanonical GTPases. It is highly conserved and present in bacteria, mitochondria, and chloropla ...[more]

PMID: 28320876

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Project description:BackgroundSP110, an interferon-induced nuclear protein, belongs to the SP100/SP140 protein family. Very recently, we showed that SP110b, an SP110 isoform, controls host innate immunity to Mycobacterium tuberculosis infection by regulating nuclear factor-?B (NF-?B) activity. However, it remains unclear how the structure of SP110 relates to its cellular functions. In this study, we provide experimental data illustrating the protein domains that are responsible for its functions.MethodsWe examined the effects of SP110 isoforms and a series of deletion mutants of SP110 on transcriptional regulation by luciferase reporter assays. We also employed confocal microscopy to determine the cellular distributions of enhanced green fluorescent protein-tagged SP110 isoforms and SP110 mutants. In addition, we performed immunoprecipitation and Western blotting analyses to identify the regions of SP110 that are responsible for protein interactions.ResultsUsing reporter assays, we first demonstrated that SP110 isoforms have different regulatory effects on NF-?B-mediated transcription, supporting the notion that SP110 isoforms may have distinct cellular functions. Analysis of deletion mutants of SP110 showed that the interaction of the N-terminal fragment (amino acids 1-276) of SP110 with p50, a subunit of NF-?B, in the cytoplasm plays a crucial role in the down-regulation of the p50-driven tumor necrosis factor-? (TNF?) promoter activity in the nucleus, while the middle and C-terminal regions of SP110 localize it to various cellular compartments. Surprisingly, a nucleolar localization signal (NoLS) that contains one monopartite nuclear localization signal (NLS) and one bipartite NLS was identified in the middle region of SP110. The identification of a cryptic NoLS in the SP110 suggests that although this protein forms nuclear speckles in the nucleoplasm, it may be directed into the nucleolus to carry out distinct functions under certain cellular conditions.ConclusionsThe findings from this study elucidating the multidomain structure of the SP110 not only identify functional domains of SP110 that are required for transcriptional regulation, cellular translocation, and protein interactions but also implicate that SP110 has additional functions through its unexpected activity in the nucleolus.

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Taking a Step Back from Back-Translocation: an Integrative View of LepA/EF4's Cellular Function.

Publications

Taking a Step Back from Back-Translocation: an Integrative View of LepA/EF4's Cellular Function.

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