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Review
. 2022 Apr 28;11(9):1482.
doi: 10.3390/cells11091482.

The Role of KH-Type Splicing Regulatory Protein (KSRP) for Immune Functions and Tumorigenesis

Kim-Alicia Palzer  1 , Vanessa Bolduan  2 , Rudolf Käfer  1 , Hartmut Kleinert  1 , Matthias Bros  2 , Andrea Pautz  1
Affiliations
Review

The Role of KH-Type Splicing Regulatory Protein (KSRP) for Immune Functions and Tumorigenesis

Kim-Alicia Palzer et al. Cells. .

Abstract

Post-transcriptional control of gene expression is one important mechanism that enables stringent and rapid modulation of cytokine, chemokines or growth factors expression, all relevant for immune or tumor cell function and communication. The RNA-binding protein KH-type splicing regulatory protein (KSRP) controls the mRNA stability of according genes by initiation of mRNA decay and inhibition of translation, and by enhancing the maturation of microRNAs. Therefore, KSRP plays a pivotal role in immune cell function and tumor progression. In this review, we summarize the current knowledge about KSRP with regard to the regulation of immunologically relevant targets, and the functional role of KSRP on immune responses and tumorigenesis. KSRP is involved in the control of myeloid hematopoiesis. Further, KSRP-mediated mRNA decay of pro-inflammatory factors is necessary to keep immune homeostasis. In case of infection, functional impairment of KSRP is important for the induction of robust immune responses. In this regard, KSRP seems to primarily dampen T helper cell 2 immune responses. In cancer, KSRP has often been associated with tumor growth and metastasis. In summary, aside of initiation of mRNA decay, the KSRP-mediated regulation of microRNA maturation seems to be especially important for its diverse biological functions, which warrants further in-depth examination.

Keywords: KH-type splicing regulatory protein; T helper cell; antiviral response; cytokine; mRNA decay; micro RNA; post-transcriptional gene regulation; tumorigenesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
KSRP structure. Schematic overview of KSRP protein structure, including the domain organization in the central region, involved in RNA interaction, and the two N- and C-terminally flanking regions, which are necessary for protein interaction. Phosphorylation sites are indicated (own illustration inspired by [10]).
Figure 2
Figure 2
KSRP regulates gene expression on various levels. In the nucleus, KSRP functions as a transcription and splicing factor, and in the cytoplasm mediates rapid decay of ARE-containing mRNAs by recruiting enzymes and silences translation of mRNAs. Moreover, KSRP promotes miRNA maturation by interacting with the ribonucleases Drosha and Dicer (own illustration inspired by [12]).
Figure 3
Figure 3
KSRP coregulates PMN migration. Bone marrow cells derived from WT and KSRP−/− mice towards C-X-C motif chemokine ligand 1 (CXCL1) were assessed in a transwell (Ø 5 µm) migration assay. Bone marrow derived cells were cultivated in 24-well plates with Iscove’s Modified Dulbecco’s Medium supplemented with 5% FCS, 1% penicillin/streptavidin, 2 mM L-Glutamin and 50 µM β-Mercaptoethanol, in a final concentration of 5 × 105 cells/mL. Seeded cells were stimulated with 250 ng/mL CXCL1. Control (Ctrl): w/o chemokine. After incubation for 4 h at 37 °C and 10% CO2, the frequency of migrating Ly6G+ PMN was assessed by flow cytometric analysis (mean + SEM, n = 6; * p < 0.05).
Figure 4
Figure 4
Expression of GATA-3 in stimulated CD4+ T cells is not affected by KSRP deficiency. Splenic CD4+ T cells (WT, KSRP−/−) were isolated by magnetic bead separation, and were polyclonally stimulated with agonistic CD3- (1 µg/mL) and CD28- (2 µg/mL) specific antibodies for 72 h. Transcription factor expression was delineated by intracellular flow cytometric analysis. Data denote the frequencies of transcription factor-positive CD4+ T cell (mean + SEM, n = 4).
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Grants and funding

This research was funded by DFG, grant number BR 3880/4-1, PA 1933/7-1, PA 1933/2-3 and KL1020/10-1 (to HK).

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