Protein

Prions are viewed as disastrous for cells; unbreakable, infectious, clumps of protein that self-propagate leading to toxic gain or loss of function. However, researchers from Stanford University have discovered a new role for prions in transmitting epigenetic information and promoting proliferation.

Proteins that have undergone a permanent conformational change are called prions. This change can trigger nearby proteins to flip and form a mass. This creates an ongoing loop that can persist over time. Prions are implicated in diseases such as Alzheimer’s, Kuru and the infamous Mad Cow Disease – Bovine Spongiform Encephalopathy.

Although normally considered detrimental, prions are used as an adaptive mechanism to respond to environmental changes in budding yeast, Saccharomyces cerevisiae. These changes are heritable, mitotically and meiotically, affecting not just the individual but their progeny.

The study looked at a particular RNA Binding Protein called SMAUG (or Vts1) that is widely conserved from Drosophila to humans. RNA Binding Proteins contain ordered regions which interact with the RNA and separate disordered regions. These disordered regions have largely unknown purposes but are found in many proteins such as SMAUG. Due to these disordered regions proteins can condense together and are prone to forming prion-like structures or condensates. SMAUG forms condensates in S. cerevisiae that self-propagate and have also been shown to drive transgenerational epigenetic inheritance.

Transgenerational epigenetic inheritance refers to changes that affect the underlying DNA without altering it, but these changes are passed on for several generations -from grandfather to grandson for example.

SMAUG readily alters its conformation and is reversible, unlike classic prions. One conformation of the protein, referred to as SMAUG+, degrades unique RNA targets. The result of this unique degradation is the altered transcription of hundreds of genes – and a protein conformation that persists through multiple generations. This conformation is infectious and heritable. When artificially made SMAUG+ was introduced to naïve cells, natural SMAUG+ condensates formed – hinting at a method of triggering epigenetic inheritance.

Although this study was performed in yeast, the researchers point out that the human homolog of SMAUG can also form reversible condensates. As over 50% of RNA Binding Proteins contain disordered regions, these prion-like proteins may have a larger role in epigenetics and inheritance than first thought – and potentially lead to a rebranding of prions away from deadly disease.

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