Regulation of B cell development and function by microRNA-191
Final Report Abstract
The initial goal of the grant – to explore the regulatory function of miR-191 in B-cell lineage – developed as initially planned. The main hypothesis has been corroborated. In the respective paper, we described the impact of miR-191 on the transcriptional regulatory network and posttranscriptional gene regulation. The transcription factors FoxP1, E2A and Egr1 were identified as direct downstream targets of miR-191. Deletion, as well as ectopic expression of miR-191, resulted in a developmental arrest in B lineage cells, indicating that miR-191 acts as a rheostat for transcriptional factors crucial for early B-cell development. It is in line with a proposed, but not welldocumented role of miRNAs in fine-tuning and stabilising transcriptional factor networks. MiR-191 allows for timely and precise regulation of crucial processes like the proliferative expansion of progenitors, responsiveness to survival cues as well as expression of key components of the recombination machinery. In parallel to the initially presented proposal, I participated as the main investigator in two other projects. The primary goal of these inquires was to delineate mechanisms behind primary immunodeficiencies caused by mutations in the LAMTOR2 and FCHO1 genes. Finally, in a project conducted by Laura Frey, we were elucidating the molecular mechanism behind VPS45 immunodeficiency. In the first of those projects, where LAMTOR2 was in the centre of our attention, we concluded that the absence of this lysosomal adaptor results in aberrant internalisation of BCR from the cell membrane, subsequently leading to abnormal phosphorylation of BCR-associated kinases. These observations are in line with human patients, where hypomorphic mutation allows for residual protein expression leading to a partial block in B-cell development and defects in class-switch recombination. This, combined with the defect in the formation of memory cells, support the idea that LAMTOR2 controls BCR signalling in both mice and human. Further, by studying the case of unknown entities, we provided evidence for an unexpected and critical role of FCHO1 in orchestrating the T-cell development and activation. These studies exemplify how systematic queries of the genetic background of congenital disorders are helping to uncover the importance of proteins and pathways, previously not associated with the function of the immune system. Furthermore, given the impact and significance of FCHO1 on lymphocyte biology, I aim to further investigate how FCHO1-mediated changes in membrane architecture regulate T-cell function.
Publications
- LAMTOR2 (p14) controls B cell differentiation by orchestrating endosomal BCR trafficking. Front Immunol (eCollection 2019)
Łyszkiewicz M, Kotlarz D, Ziętara N, Brandes G, Diestelhorst J, Glage S, Hobeika E, Reth M, Huber L.A., Krueger A, Klein C
(See online at https://doi.org/10.3389/fimmu.2019.00497) - miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity. PLoS Biology (eCollection 2019)
Łyszkiewicz M, Winter SJ, Witzlau K, Föhse L, Brownlie R, Puchałka J, Verheyden N, Kunze- Schumacher H, Imelmann E, Blume J, Raha S, Sekiya T, Yoshimura A, Frueh J, Ullrich E, Huehn J, Weiss S, Gutierrez MG, Prinz I, Zamoyska R, Ziętara N, Krueger A
(See online at https://doi.org/10.1371/journal.pbio.2006716) - miR-191 modulates B-cell development and targets transcription factors E2A, Foxp1, and Egr1. Eur J Immunol, 49: 121–132 (2019)
Blume J, Ziętara N, Witzlau K, Liu Y, Sanchez OO, Puchałka J, Winter SJ, Kunze-Schumacher H, Saran N, Düber S, Roy B, Weiss S, Klein C, Wurst W, Łyszkiewicz M, Krueger A
(See online at https://doi.org/10.1002/eji.201847660) - Human FCH domain only 1 (FCHO1) deficiency reveals an essential role for clathrin-mediated endocytosis for the development and function of T cells. Nat Commun (2020)
Łyszkiewicz M, Ziętara N, Frey L, Pannicke U, Liu Y, Fan Y, Puchałka P, Hollizeck S, Somekh I, Rohlfs M, Yilmaz T, Ünal E, Karakukcu M, Patiroğlu T, Keller C, Karasu E, Sykora K-W, Somech R, Roesler J, Hoenig M, Schwarz K, Klein C
(See online at https://doi.org/10.1038/s41467-020-14809-9) - Mammalian VPS45 orchestrates trafficking through the endosomal system. Blood
Frey L, Zietara N, Łyszkiewicz M, Marquardt B, Mizoguchi Y, Linder MI, Liu Y, Giesert F, Wurst W, Dahlhoff M, Schneider M, Wolf E, Somech R, Klein C
(See online at https://doi.org/10.1182/blood.2020006871)
