The ubiquitin proteasome system (UPS) is the major regulatory system that maintains the homeostasis of the cellular proteome. It controls the stability, sub-cellular location and activation of a large cross-section of cellular proteins. The multiplicity in ubiquitin function provides immense regulatory capacity not limited to only protein degradation. There is a growing body of work suggesting that capture of polyubiquitin chains on substrates by so-called ‘ubiquitin receptors’ is a well-regulated step critical to many cellular processes. Dysfunction of the UPS particularly at the ubiquitin recognition step can lead to the inappropriate accumulation of substrates, perturbation in the balance of the proteome and proteotoxic stress. Thus, understanding how the UPS system coordinates protein quality control may identify strategies to target vulnerabilities in human disease, especially in protein aggregation disorders.
Our group is interested in understanding mechanisms that regulate protein quality control. In particular we study how the VCP AAA-ATPase (also known as p97 or Cdc48) functions to triage proteins post-translationally modified by ubiquitin.
Journal Club. Fridays at 4pm.
10.20.17 FAF1 phosphorylation by AKT accumulates TGFb type II receptor and drives breast cancer metastasis. Xie et al., Nature Communications 2017. 07.01.17 An aberrant phase transition of stress granules triggered by misfolded protein and prevented by chaperone function. Mateju et al., EMBO 2017.
06.09.2017 Molecular Mechanism of Substrate Processing by the Cdc48 ATPase Complex.Bodnar and Rapoport, Cell 2017
Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy.Blythe et al, PNAS 2017
05.12.17 Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. Lee at al Cell Reports 2017
04.07.12 The N-terminal Region of the Ubiquitin Regulatory X (UBX) Domain-containing Protein 1 (UBXD1) Modulates Interdomain Communication within the Valosin-containing Protein p97.Trusch et al JBC 2015.
03.31.17 Peroxin dependent targeting of a lipid-droplet destined membrane protein to ER subdomains Schrul and Kopito Nature Cell Biology 2016.
03.24.17 Newly born peroxisomes are a hybrid of mitochondrial and ER-derived pre-peroxisomes.Sugiura A. et al Nature 2017
02.13.17 Mechanistic basis for a molecular triage reaction Shao S. et. al Science 2017 01.03.17 ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation.Sundaramoorthy et al Mol Cell 2017.
01.13.2017 Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor. Wei et.al. Cell, 2016.
01.06.17 VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy Papadoupolous et al. EMBO, 2016.