Research group Magdalena Paolino

We apply innovative techniques to model diseases and alter the functions of genes in order to reveal the underlying molecular bases of disease pathogenesis, primarily cancer, immune related disorders, as well as cardiometabolic and intestinal diseases. Currently, our focus is placed on unraveling the diverse roles of protein ubiquitination in preventing or driving those diseases. Our ultimate aim is to provide novel opportunities for more effective and specific therapeutic strategies.

Genes function and molecular bases of diseases 

We are dedicated to studying the molecular mechanisms regulating normal physiology as well as disease pathogenesis. We do this by combining advance animal models with genetic and molecular approaches. Our research is multidisciplinary and comprehensive, going all way from genes and molecules to cells, genetically engineered mice and preclinical studies. We primarily use loss-of-function mutant mice to reveal the role of genes in disease mouse models, and combine them with cellular and molecular techniques, such as flow cytometry, histology, molecular biology and cell culture. We also use ex vivo specialized primary cultures, including 3D organoids, virus-based gene editing, and omic technologies. We focus our studies in the fields of cancer, immunology, intestinal biology as well as cardiometabolic diseases, with a particular molecular interest for exploring how the process of protein ubiquitination participate in physiology and disease pathogenesis.

 Ongoing research

Structural representation of ubiquitin, highlighting secondary structures and the residues of Lysine and Methionine (blue and yellow balls and sticks, respectively) that are used to form up to eight structurally different polyubiquitin chains; each with presumptive distinct cellular functions. Artwork: by Matias Machado, using VMD software.

Ubiquitination in physiology and disease: Even though numerous human pathologies are linked to alterations in the process of ubiquitination, an essential posttranslational protein modification, we still do not fully understand the true complexity, specificity, and dynamics of the ubiquitin code. Specifically, the cellular and physiological processes regulated by many deubiquitinating enzymes, the enzymes that remove ubiquitination, as well as the pathophysiological roles of atypical ubiquitin chains, chains of ubiquitin linked by lysines (K) K6, K27, K29, K33, remain obscure. Our current main research aims to narrow these knowledge gaps. We are undertaking diverse projects to revealing the functions and impact of atypical ubiquitination and the related deubiquitinases in intestinal homeostasis, cancer, immune related disorders and cardiometabolic diseases.

Gender dimorphism: We recently revealed how the thymus stroma adapts to integrate the hormonal, immune and metabolic responses of pregnant females mice, safeguarding via the immune system the development of the embryos (Nature 2021). We keep interested in this line of research and have also projects aiming to better understand gender dimorphism in relation to immune and cardiometabolic diseases.

The significance of our research

 Comprehensive preclinical studies using model organisms are essential to identify new disease-related genes, better understand the complexity and etiology of diseases and can also serve as platforms for drug discovery programs. Our integrative approach to use functional genetics analyses to provide thorough in vivo and mechanistic insights will increase our molecular understanding of the pathogenesis of diseases and could set the molecular basis for the design of novel strategies for therapies.

Group members

Lab team Paolino.
Photo: N/A. The Paolino Group, Summer 2021. From left: Hang Yu, Jianing Liu, Shubhangi Gavali, Magdalena Paolino, Xinyi Li, Azad Saei.

Magdalena Paolino

Assistant Professor, research group leader

Past group members

  • Julia Andersson, Bachelor student.
  • Shubhangi Gavali, PhD, Postdoctoral fellow.
  • Anneli Olofsson, Research Assistant.
  • Azad Saei PhD, Postdoctoral fellow.
  • Hang Yu, Summer Student.

Funding

  • The Swedish Research Council.
  • Ragnar Söderbergs Foundation.
  • Cancerfonden.
  • Karolinska Institutet.

Selected publications

Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy.
Shubhangi Gavali, Jianing Liu, Xinyi Li, and Magdalena Paolino.  Int. J. Mol. Sci. 202122(19), 10800

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.
Paolino M, Koglgruber R, Cronin SJF, Uribesalgo I, Rauscher E, Harreiter J, et al
Nature 2021 Jan;589(7842):442-447

A high-efficiency and versatile CRISPR/Cas9-mediated HDR-based biallelic editing system.
Li X, Sun B, Qian H, Ma J, Paolino M, Zhang Z
J Zhejiang Univ Sci B 2022 Feb;23(2):141-152

The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.
Cronin SJF, Seehus C, Weidinger A, Talbot S, Reissig S, Seifert M, et al
Nature 2018 11;563(7732):564-568

β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1.
Suriben R, Kaihara KA, Paolino M, Reichelt M, Kummerfeld SK, Modrusan Z, Dugger DL, Newton K, Sagolla M, Webster JD, Liu J, Hebrok M, Dixit VM
Cell 2015 Dec;163(6):1457-67

The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells.
Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM
Nature 2014 Mar;507(7493):508-12

ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.
Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, et al
Nature 2012 Jul;487(7408):477-81

Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.
Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, Withers DR, et al
Immunity 2012 Mar;36(3):427-37

Cbl-b in T-cell activation.
Paolino M, Penninger JM
Semin Immunopathol 2010 Jun;32(2):137-48

Central control of fever and female body temperature by RANKL/RANK.
Hanada R, Leibbrandt A, Hanada T, Kitaoka S, Furuyashiki T, Fujihara H, et al
Nature 2009 Nov;462(7272):505-9