Pedro Carvalho

Organelle Biogenesis and Homeostasis

Accumulation of certain proteins or lipids is toxic to cells and the hallmark of diseases such as neurodegeneration and atherosclerosis. Our laboratory seeks to understand mechanisms controlling the levels and distribution of protein and lipids with the focus on two main areas: 1) the quality control processes that detect and eliminate non-functional, potentially toxic proteins. 2) the mechanisms promoting lipid storage in dedicated cellular locations thereby preventing their toxic accumulation.

The endoplasmic reticulum (ER) is the largest membrane-bound organelle in cells, playing numerous essential functions including the biogenesis of secreted and membrane proteins, lipid synthesis and assembly of the nuclear envelope. A long-term goal of my lab is to dissect how these functions are coordinated and ER homeostasis achieved. Proteolysis through the ER-associated degradation (ERAD) pathway has emerged as key in maintaining ER homeostasis and this proposal aims at understanding its mechanistic basis, with a particular focus on membrane protein substrates. ERAD is organized in multiple branches, thereby targeting a broad range of luminal and membrane substrates. The mechanisms by which luminal substrates are selected and processed by the ERAD machinery are well established. In contrast, the mechanisms by which ERAD targets membrane substrates are mysterious and several fundamental questions remain: (1) what are the preferences of the various ERAD branches for membrane substrates? (2) what are the molecular basis for their recognition? (3) how are membrane substrates translocated to cytosol for degradation? Addressing these issues will reveal key mechanisms of membrane protein quality control by ERAD. Given that defects in protein quality control are linked to various pathologies, from developmental diseases to neurodegeneration, our studies may have clinical relevance.

The ER also has a direct role in the biogenesis of other organelles, such as lipid droplets (LDs). These are ubiquitous organelles involved in storage of neutral lipids, with a key role in cellular lipid homeostasis and important connections to common diseases like obesity and atherosclerosis. However, many fundamental aspects of LD cell biology remain elusive. By studying how LDs originate at the ER, we discovered a protein complex that stabilizes the contact sites between the two organelles. Interestingly, this complex contains the lipodystrophy associated protein seipin. The mechanism by which seipin controls ER-LD contact site is currently under investigation. We are also studying how other ER membrane proteins control LD biogenesis and behaviour.

In our studies we take advantage of a variety of approaches. We regularly use quantitative proteomics, genetics, biochemistry and imaging tools using yeast and mammalian tissue culture cells as model systems.

Group members

  • Pedro Carvalho (Group leader)
  • Yutong Yang (PhD student)
  • Michael Van de Wiejer (Postdoc)
  • Yuichi Tsuchyia (Postdoc)
  • Nikita Sergejevs (PhD student)
  • Wing (Skyla) Siu (PhD student)
  • Jacob Robson-Tull (PhD student)
  • Yoel Klug (Postdoc)
  • Zhe Ji (Postdoc)
  • Joana Ferreira (PhD student)

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