Fine-tuning of autophagy nature in intestinal homeostasis
Research summary:
Inflammatory Bowel Disease (IBD) is a multifactorial condition that results from an intricate interplay of genetic predisposition, an altered immune response, changes in the intestinal microbiota and environmental factors. IBD courses with chronic inflammation of the intestine and, although its prevalence in Europe is high -and increasing-, there is not a cure for it yet due to the lack of a complete description of its etiology.
Intestinal homeostasis is established along development through the equilibrium between three cellular components: microbiota, the mucosal immune system, and the epithelial barrier. It has been proposed that IBD is a collapse of intestinal homeostasis.
Genome-wide association studies have revealed Autophagy (canonical and non-canonical) as a critical molecular pathway involved in intestine homeostasis and, therefore, as a possible therapeutic target to treat IBD. However, its precise function remains elusive still. The role of canonical and non-canonical autophagy has been addressed separately, as an isolated mechanism, giving place to misleading and contradictory conclusions. According to our previous results (N. Martinez-Martin et al., Science 355, 641 (2017)) canonical and non-canonical coexist in splenic B cells, and its fine-tune regulation is strictly needed to mount an effective systemic humoral response. In this regard, and focusing on the mucosal immune system, in our laboratory we are characterizing the ¨Autophagy Fingerprint¨ (AF) -the precise amount of canonical and non-canonical autophagy- in each B cell type, paying particular attention to the role of microbiota on AF imprinting along development.
We propose that AF exerts a cell-intrinsic function targeting mitochondria content and, therefore, affecting cell metabolism. However, AF might also play a paracrine mechanism, turning B cells into a source of signaling molecules that would act on neighboring cells and controlling in this way the intestine homeostasis. An aberrant AF might then give place to a breakdown of intestinal homeostasis, being the likely origin of IBD.
Therefore, the main aims of our group are to characterize the AF in the B cell compartment and to describe its role in the establishment and maintenance of the intestinal homeostasis and correlate it with IBD.
Our results will offer new ways to understand the molecular mechanisms controlling intestine homeostasis and their relationship with human pathologies. We expect the results derived from this study would serve for the improvement of current treatments of IBD and the development of new treatment strategies.
Figure 1: Study of the cell-intrinsic and paracrine mechanism of AF (Autophagy Fingerprint) in B cells and its role in the intestine homeostasis (ASC: Antibody Secreting cells; GC: Germinal Center)
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| Iborra Pernichi | Marta | 120 | 4517 | marta.iborra(at)cbm.csic.es | Titulado Sup. Actividades Tecn. y Prof.GP1 |
| Martínez Martín | Nuria | 120 | 4517 | nmartinez(at)cbm.csic.es | Investigador |
| Ruiz García | Jonathan | 120 | 4517 | jruiz(at)cbm.csic.es | GJ-AI_Tit. Sup. Actividades Técn. y Prof.GP1 |
| Velasco de la Esperanza | María | 4517 | mvelasco(at)cbm.csic.es | GJ-AI y TL_Titulado Sup. Actividades Técn. y Prof.GP1 |
Relevant publications:
- Ortega-Molina A, Deleyto-Seldas N, Carreras J, Sanz A, Lebrero-Fernández C, Menéndez C, Vandenberg A, Fernández-Ruiz B, Marín-Arraiza L, de la Calle Arregui C, Plata-Gómez AB, Caleiras E, de Martino A, Martínez-Martín N, Troulé K, Piñeiro-Yáñez E, Nakamura N, Araf S, Victora GD, Okosun J, Fitzgibbon J, and Efeyan A. (2019). Oncogenic Rag GTPase signalling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR. Nature Metabolism. 1(8);775-789. doi: 10.1038/s42255-019-0098-8.
- Ana Martínez Riaño; Elena Rodriguez Bovolenta; Pilar Mendoza; Clara Oeste; María Jesús Martín Bermejo; Paola Bovolenta; Martin Turner; Nuria Martínez-Martín1; Balbino Alarcón. Antigen phagocytosis by B cells required for a potent humoral response. EMBO Reports. e46016, 2018. (1 co-corresponding author).
- Carlson Tsui; Paula Maldonado; Beatriz Montaner; Borrroto, A; Balbino Alarcón; Andreas Bruckbauer; Nuria Martínez-Martín; Facundo Batista. Dynamic reorganisation of intermediate filaments coordinates early B-cell activation. Life Science Alliance. 1 - 5, 2018.
- Nuria Martínez Martín*; Carlson Tsui*; Mauro Gaya; Paula Maldonado; Mariam Llorian; Nathalie Legrave; Merja Rossi; James I MacRae; Angus J Cameron; Peter J Parker; Michael Leitges; Andreas Bruckbauer; Facundo Batista. PKC? dictates B-cell fate by regulating mitochondrial remodelling, metabolic reprogramming and heme biosynthesis. Immunity. 48, pp. 1144 - 1159. 2018. (* equally contributed).
- Nuria Martínez Martín*1; Pilar Mendoza*; Pablo Hernansanz Agustin; Pilar Delgado; Manuel Diaz Muñoz; Clara Oeste; Isabel Fernández Pisonero; Ester Castellano; Antonio Martinez Ruiz; Eugenio Santos; Tomohiro Kurosaki; Xose Bustelo; Balbino Alarcón. RRas2 is required for germinal center formation to aid B cells during energetically demanding processes. Science Signaling. 11 - 532, 2018. (* equally contributed; 1 co-corresponding author).
- Nuria Martínez-Martín*1; Paula Maldonado*; Francesca Gasparrini; Bruno Frederico; Carlson Tsui; Mariane Burbage; Shweta Aggarwal; Mauro Gaya; Beatriz Montaner; Harold B.J Jefferies; Selina Keppler; Usha Nair; Yan Zhao; Marie-Charlotte Domart; Lucy Collinson; Andreas Bruckbauer; Sharon Tooze; Facundo Batista. 2017. A switch from canonical to non-canonical autophagy shapes B cell responses. Science. Vol 355 – 6325. Pp 641-647. (* equally contributed; 1 co-corresponding author).
Funding:
- Spanish Ministry of Economy and Business (MINECO) – (Programa Retos de la sociedad, 2018-2021)
- Comunidad de Madrid, Programa de Garantía Juvenil 2019 – Ayudante de Investigación
