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Membraneless organelles in cell biology

Cells are highly compartmentalized to limit biochemical reactions in space. A large component of cell compartmentalization is provided by membrane-bound organelles, that is, organelles that are surrounded by a sealed lipid bilayer. The membrane defines the boundary of the organelle, separating the lumen from the surrounding cytoplasm and limiting the biochemical/enzymatic reactions that are catalyzed by the organelle. Compartmentalization also allows for interactions with a specific pool of cytoplasmic proteins that are peripherally associated with the membrane. Together, these features define key aspects of the functional identity of membrane-bound organelles. This, together with their biogenesis, their maintenance and how they function and communicate—collectively referred to as membrane traffic—has been extensively studied in the last four decades and has yielded a Nobel Prize in Physiology and Medicine in 2013. The second type of stable cellular compartments is the so-called membraneless organelles (referring to the fact that they are not sealed by a membrane). Membraneless organelles have recently (re-)gained the attention of biophysicists for their unique mechanism of formation by phase separation and for their material properties. Indeed, phase separation can either be liquid/liquid or liquid/solid. The consensus is that the phase separation is driven by both multivalent proteins displaying intrinsically disordered domains and RiboNucleic Acids (RNAs). Membraneless organelles are different from cytoplasmic assemblies such as ribosomes, proteasomes and hsp60 complexes, which have a fixed and defined subunit stoichiometry and are quaternary assemblies. Phase-separated membraneless organelles are considered to be quinary assemblies, thus referring to their variable composition and to the affinity between their components that can be low. Although their phase separation is mostly studied in vitro, membraneless organelles are present in both the cell nucleoplasm and cytoplasm of most eukaryotes, and they carry out important functions. Like membrane-bound organelles, membraneless organelles appear to support specific biochemistries with critical functions in cellular homeostasis and development. This special issue of Traffic contains a series of reviews documenting cytoplasmic membraneless organelles in their cellular environment and in vivo. Marnik and Updike have contributed a review about germ granules Caenorhabditis elegans, which are called P granules. P granules are a mix of RNA molecules and proteins. They ensure the integrity of germ cells and are required for fertility in the adult. They have the properties of liquid droplets, and their phase separation appears to rely on proteins with intrinsically disordered regions, such as P granule abnormality and maternal effect germ-cell defective. In the same line, Trcek and Lehmann have written a review about germ granules in Drosophila germ cells. These are formed during oogenesis and persist into embryogenesis. Their phase separation relies on scaffold proteins that recruit effector messenger RNAs (mRNAs) and Piwi-interaction RNAs (piRNAs), which instruct the germ cell fate. As such, they act as the gatekeeper of the next generations. Neuronal granules are another class of membraneless organelles. They are enriched in RNA molecules that are associated with regulatory proteins. Formicola, Vijayakumar and Besse have described how they form in neurons and are transported along microtubules to dendrites and axons, during which they are translationally silent. However, in response to external cues, neuronal granules undergo remodeling and specifically activate the translation of granule-associated mRNAs in a timeand space-dependent manner, a process critical for neuronal activity. While membraneless compartments have important functions in cell (neurons) physiology, they can become pathological when formed on the expression of mutated proteins and/or when cells are exposed to stress. The same review describes how this can lead to abnormal aggregation of granule components, as is observed in pathological contexts, and is thought to underlie the progression of neurodegenerative diseases. Interestingly, aberrant phase separation also seems to occur in cancer as reported in the review from Spannl et al. Animal cells, plants, algae and photosynthetic organisms also have membraneless organelles that are critical for their homeostasis, such as the non-RNA-based pyrenoid described by Wunder, Oh and Mueller-Cajar. The formation of this compartment by phase separation relies on the CO2-fixing enzyme Rubisco, which enables a localized concentration of the gaseous substrate. It also relies on an intrinsically disordered linker protein, both in vivo and in vitro. This reconstitution approach gives a new angle to the biochemical characterization of the pyrenoid matrix. Finally, many reversible membraneless compartments are also strongly induced by cellular stress such as oxidative, endoplasmic reticulum, proteostatic, osmotic and nutrient stress. The two best studied stress assemblies are the RNA-based P-bodies and stress granules. Although they are different compositions, they often overlap and exchange RNAs. They both act as sites for RNA storage, as well as protecting the RNA against degradation (stress granules) or repressing their translation (P-bodies). Both are subcompartmentalized and heterogeneous with respect to the DOI: 10.1111/tra.12686