Discovering the cellular RNA-binding proteins controlling virus infection

Our new research published in Molecular Cell has uncovered that virus infection rewires cellular RNA-binding proteins (RBPs) on a global level. This reflects two antagonistic processes: the virus hijacking key cellular resources and the antiviral defence mechanisms of the cell. We discovered dozens of RBPs that play central roles in virus infection and opens new avenues for the development of antiviral therapies. Find out more about this work here.

Original article

System-wide profiling of RNA-binding proteins uncovers key regulators of virus infection. Garcia-Moreno M*,  Noerenberg M*, Ni S*,  Järvelin AI, González-Almela E, Lenz CE, Bach-Pages M, Cox V, Avolio R, Davis T, Hester S, Sohier TJM, Li B, Heikel G, Michlewski G,  Sanz MA, Carrasco L, Ricci EP, Pelechano V, Davis I, Fischer B, Mohammed S and Castello A. Molecular Cell. DOI: https://doi.org/10.1016/j.molcel.2019.01.017
https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30037-1

Riboregulation: when RNA controls protein function

It is established that interactions of proteins with RNA play a crucial role at regulating RNA fate. However, a recent work led by the Hentze lab at EMBL has discovered that the reverse relationship is also possible. In other words, proteins can be regulated by RNA. We refer to this phenomenon as ‘riboregulation’.

This study shows that the RNA vault 1-1 (vtRNA1-1) interacts and regulates the protein p62, which is a key component of the autophagy machinery. As its name suggests, autophagy is a process by which a cell ‘eats itself’ to recycle its unnecessary or dysfunctional components. Interaction of vtRNA1-1 with p62 inhibits autophagy and this regulatory circuit exists in both human and mouse cells.

Importantly, the amount of vtRNA1-1 inside a cell varies according to the cell’s nutritional status. When is deprived of amino acids, vtRNA1-1 is reduced to enhance autophagy that will refill the pool of amino acids from unnecessary proteins to cover the cell needs.

This study raises the question of how common ‘riboregulation’ is and which processes are controlled by RNA. We hope to find the answer to these important questions in the years to come.

Original publication

The Small Non-coding Vault RNA1-1 Acts as a Riboregulator of Autophagy. Horos R, Büscher M, Kleinendorst R, Alleaume AM, Tarafder AK, Schwarzl T, Dziuba D, Tischer C, Zielonka EM, Adak A, Castello A, Huber W, Sachse C, Hentze MW. Cell. 2019 Feb 21;176(5):1054-1067.e12. doi: 10.1016/j.cell.2019.01.030. Epub 2019 Feb 14.PMID: 30773316

Developing a successful part II project

Jess and Morgan have worked in their part II projects for near six months in the Castello lab. They have studied different aspects of HIV biology by using cutting edge RNA biology, virology, molecular biology and microscopy techniques. Morgan has developed a new approach to elucidate the composition of the HIV ribonucleoproteins. Jess has assessed whether cellular RNA-binding proteins are incorporated into HIV particles. We hope they enjoyed working in the lab and wish them all the best for the coming scientific challenges.

Princeton student visit the Castello lab

Leslie worked in the Castello lab for five months as part of her degree in Princeton. She was interested in the understanding the role of a family of tumour suppressors recently classified as RNA-binding proteins by RNA interactome studies.

“Applying for this semester-long research opportunity at Oxford is one of the best decisions I have made at Princeton!  I am constantly intellectually stimulated and challenged by my research project and my PI’s thoughtful feedback – said Leslie-.  In my lab’s supportive environment,  I have come to really appreciate microscopy, beautiful silver staining/Western blot gels, the satisfying popping sound in the homogenizing process of my RNA interactome capture whole cell lysates, and so much more!  Would definitely consider coming back for grad school!”