Arno Alpi

Investigating ubiquitin-signalling and proteostasis in cell differentiation.

Arno Alpi is a Senior Lecturer and Group Leader at the Institute of Cell Biology. He studied Biochemistry at the University of Vienna and received his PhD at the Max-Planck Institute of Biochemistry and the Ludwig-Maximilian University of Munich, followed by a Postdoctoral study with Prof KJ Patel at the MRC-LMB, Cambridge. 

Arno then headed labs at the MRC-PPU, University of Dundee, and the Max-Planck Institute of Biochemistry, Munich, before moving back to Scotland in Spring 2024 to join the Institute of Cell Biology at the University of Edinburgh. 

portrait photo of Arno Alpi
Arno Alpi

Fengqianrui Chen


Our major scientific focus is to understand signalling pathways controlled by ubiquitylation – a protein modification utilizing the small protein “ubiquitin” – known to impact the protein’s fate, such as its turnover and stability, subcellular location, assembly, conformation and activity. We combine integrative omics approaches, biochemistry, and cell biology to functionally dissect these ubiquitin signalling pathways and their molecular machines, aiming to understand their physiology and how their deregulation promotes cellular transformation and disease.

Ubiquitin signalling in red blood cell development

Human red blood cell (RBC) development is a multistep process that maintains stable erythroid homeostasis throughout life and replenishes more than 200 billion erythrocytes lost by senescence in healthy humans. Throughout this process, many RBC-specific proteins are initially expressed, but then all cellular organelles and the majority of proteins are eventually eliminated in a stepwise fashion. We recently identified and characterized the multiprotein CTLH E3 ubiquitin ligase complex as key regulator of balancing dormancy of RBC progenitors and their terminal differentiation into enucleated mature RBC. To determine the mechanism of CTLH E3 function, we identified several CTLH E3-specific protein targets associated with metabolisms and gene regulation. Using cell culture systems to reconstitute RBC differentiation in-vitro, we aim to dissect CTLH E3 function in metabolic rewiring during RBC differentiation, as well as changes in the chromatin landscape (Figure 1).

Figure 1.


Red Blood Cell differentiation
Red Blood Cell Differentiation

Defective ubiquitin system in intellectual disability syndrome

Recently, pathogenic variants of subunits of the CTLH E3 ligase complex have been associated with neurodevelopmental disorders, including the Skraban-Deardorff intellectual disability syndrome. Building on our advances of the structure and mechanism of CTLH E3 ligases we aim to dissect the pathophysiological mechanism of Skraban-Deardorff syndrome. We combine human iPSC-derived neuronal cell system, somatic genetics, cell biology, and biochemical approaches to uncover how lesions in subunits affect the assemblies of the CTLH E3 complex and dissect its functional roles in neuronal development.

Gottemukkala KV, Chrustowicz J, Sherpa D, Sepic S, Vu DT, Karayel Ö, Papadopoulou EC, Gross A, Schorpp K, von Gronau S, Hadian K, Murray PJ, Mann M, Schulman BA, Alpi AF (2024) Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism. Mol Cell. 2024 May 16;84(10):1948-1963.e11.

Gross A, Müller J, Chrustowicz J, Strasser A, Gottemukkala KV, Sherpa D, Schulman BA, Murray PJ, Alpi AF (2024) Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly. FEBS Lett. 2024 May;598(9):978-994.

Sherpa D, Müller J, Karayel Ö, Chrustowicz J, Xu P, Yao Y, Gottemukkala KV, Baumann C, Gross A, Czarnezki O, Zhang W, Gu J, Nilvebrant J, Weiss MJ, Sidhu SS, Murray PJ, Mann M, Schulman BA, Alpi AF (2022) Modular UBE2H-CTLH E2-E3 complexes regulate erythroid maturation. eLife 2022;11:e77937


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