MRC Protein Phosphorylation and Ubiquitylation Unit

Genetic and pharmacologic inhibition of Keap1 dampens the pro-fibrotic program in human hepatic stellate cells

Abstract The increasing prevalence of chronic liver diseases (CLDs) is a global health concern. CLDs can cause fibrosis, and there is an urgent need for antifibrotic agents. The primary driver of fibrogenesis, transforming growth factor beta 1 (TGF-β1), activates hepatic stellate...

Functional pathway phenotyping reveals increased LRRK2 activity beyond recognised genetic causes of Parkinson’s disease

Abstract Pathogenic LRRK2 variants cause Parkinson’s disease (PD) through increased kinase activity, with VPS35 p.D620N and other emerging genetic factors also increasing LRRK2 signalling. Findings in idiopathic PD also suggest broader LRRK2 pathway involvement. As LRRK2-targeted...

Reconstitution of multistep recruitment of ULK1 to membranes in autophagy

Abstract The Human ULK1 autophagy-initiating complex consists of ULK1, FIP200, and the HORMA domain heterodimer ATG13:ATG101. PI3P is essential to recruit ULK1C to membranes for ULK1, but ULK1C subunits do not contain PI3P-binding domains. Here we show that the ATG13:ATG101 dimer...

The c‐Src inhibitor eCF506 diminishes opioid tolerance and reduces β‐arrestin2 recruitment

Background and Purpose Opioids, such as morphine, are effective analgesics, but their persistent use is compromised by tolerance. In mice, tolerance is attenuated by β‐arrestin2 depletion or Src‐family kinase inhibitors, which may act through off‐target effects. We tested the eff...

FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators

Abstract VCP/p97 is an AAA+ ATPase that, together with its cofactors UFD1-NPL4 (p97-UN), unfolds ubiquitylated substrates to maintain cellular homeostasis. The human p97-UN complex associates with additional cofactors, but how these cofactors modulate p97-UN activity is not fully...

USP5 acts as a proteolytic switch to control SDE2 function via UBL-directed cleavage

Abstract Proteolytic processing is a fundamental regulatory mechanism in eukaryotic cells, yet the molecular identities and mechanisms underlying such events are often poorly defined. Silencing Defective 2 (SDE2), an essential human protein, plays important roles in mRNA splicing...