What’s special about mRNA storage?
An egg can be stored for years in the animal’s body before it’s released to be fertilised or eliminated. For example, in humans, all eggs are already made in a newborn girl, but they are kept inactive until the girl’s menstrual cycles begin and potentially until decades later. mRNAs stored inside those eggs need to stay inactive, too, otherwise the eggs might fill up with unused proteins and die.
How did you find a protein that enables safe storage?
RNA has a similar structure to DNA: it’s a string of bases or ‘letters’. At one end of this string is a sequence of about 200 ‘As’, called a poly(A) tail, and at the other end, a protective cap made of a modified base. One way that mRNAs can be degraded is when the mRNA cap is removed – this triggers the rest of the string to be degraded.
So, in this study, I pinpointed a set of factors that bind to the RNA cap, thinking they might help stabilise it. Among these factors, I found one that is specific to the early stages of egg development and early embryogenesis. This factor is called eIF4E1b – it’s the protein I focused my experiments on, with a lot of help from Marcus Strobl, one of my co-authors.
What is the poly(A) tail for?
It plays a role for the translation and stability of mRNAs. The length of the tail usually determines how stable the mRNA is: the shorter the tail, the more exposed the mRNA to degradation. However, maternal mRNAs stored in the egg have short poly(A) tails, and yet they’re very stable. This means there must be protective factors involved.
The length of the tail also determines the amount of translation that can happen with this mRNA. A longer tail leaves more space for RNA-binding proteins to bind and launch translation. Egg mRNAs have a short poly(A) tail to prevent translation from happening too early.
What does eIF4E1b do to keep mRNAs stable?
This protein has a ‘cousin’ protein in somatic cells that is known to bind the mRNA cap and contribute to initiating translation. In previous studies, the egg version of the protein was found not to bind the cap. In this publication, I used other protein purification tools and I show the opposite: eIF4E1b does bind the mRNA cap.
Did you find anything surprising about the protein’s function?
The somatic version of the protein binds a factor that promotes translation, but eIF4E1b doesn’t. Instead, it contributes to repressing translation, which makes sense in the context of mRNA storage. The protein helps maternal mRNAs with short poly(A) tails to remain stable, allowing the egg to develop normally. When eIF4E1b is mutated in zebrafish, I found that eggs don’t develop properly, and all fish turn into males. In mouse, mutated eIF4E1b makes females sterile. The next steps will be to understand the exact mechanisms by which eIF4E1b selects mRNAs or releases them from dormancy.
Laura Lorenzo-Orts#, Marcus Strobl, Benjamin Steinmetz, Friederike Leesch, Carina Pribitzer, Josef Roehsner, Michael Schutzbier, Gerhard Dürnberger, and Andrea Pauli#: “eIF4E1b is a non-canonical eIF4E protecting maternal dormant mRNAs”. EMBO Reports (2023). DOI: 10.1038/s44319-023-00006-4.