Proteostasis in Stem Cells

Our research

Proteostasis is an essential biological process and plays a major role in the regulation of stem cells. We are particularly interested in the ubiquitin–proteasome system (UPS), which plays a crucial role in regulating the abundance of most cellular proteins. Substrate specificity in this system is governed by a large family of around 600 E3 ubiquitin ligases, which direct the degradation of specific target proteins and thereby shape essential cellular functions. Using hematopoietic stem cells as a model, we explore how the UPS influences stem cell fate decisions and perturbations in these pathways leads to malignant transformation. Building on this foundation, we are also developing targeted protein degradation–based tools, both to interrogate the function of protein complexes and to target therapeutically relevant proteins that are currently inaccessible to conventional drugs. 

Aims

• To uncover the E3 ubiquitin ligases and degradation pathways that control hematopoietic stem cell self-renewal and differentiation
• To uncover perturbations in protein degradation pathways that lead to tumorigenesis, with a focus on leukemia and medulloblastoma
• To employ targeted protein degradation-based research tools to reveal the regulatory roles of protein complexes in hematopoietic stem cells 

Impact

By connecting the regulated turnover of proteins to stem cell fate, our work aims to reveal fundamental principles of how cells balance self-renewal, differentiation, and transformation. This has direct relevance for two areas of unmet medical need. In regenerative medicine, understanding how degradation pathways drive stem cell expansion could improve strategies for stem cell–based therapies, such as cord blood transplantation and ex vivo gene therapies. In oncology, the same insights open the door to targeting proteins long considered "undruggable", offering new therapeutic avenues for high-risk tumours, including childhood brain tumours, where treatment options remain limited. Ultimately, we hope to both deepen the fundamental understanding of proteostasis in stem cells and reveal new vulnerabilities that can be exploited to treat cancer.

Team

(name linked to profile in Lund University research portal)

Agatheeswaran Subramaniam

Principal Investigator, agatheeswaran [dot] subramaniam [at] med [dot] lu [dot] se (agatheeswaran[dot]subramaniam[at]med[dot]lu[dot]se)

Kristijonas Zemaitis

Postdoctoral Fellow, kristijonas [dot] zemaitis [at] med [dot] lu [dot] se (kristijonas[dot]zemaitis[at]med[dot]lu[dot]se)

Neelanjana Sarkar

Postdoctoral Fellow, neelanjana [dot] sarkar [at] med [dot] lu [dot] se (neelanjana[dot]sarkar[at]med[dot]lu[dot]se)

Rohit Sivaprasad

Doctoral Student, rohit [dot] sivaprasad [at] med [dot] lu [dot] se (rohit[dot]sivaprasad[at]med[dot]lu[dot]se)

Isabela Bouzková

Student working on a degree project, isabela [dot] bouzkova [dot] 7071 [at] student [dot] lu [dot] se (isabela[dot]bouzkova[dot]7071[at]student[dot]lu[dot]se)

Jan Novoselec

Student working on a degree projectjan [dot] novoselec [dot] 8163 [at] student [dot] lu [dot] se (, jan[dot]novoselec[dot]8163[at]student[dot]lu[dot]se)

Simona Yordanova

Student working on a degree project, simona [dot] yordanova [at] med [dot] lu [dot] se (simona[dot]yordanova[at]med[dot]lu[dot]se)