Rico Schieweck1,2 and Magdalena Götz2,3,4 1Institute of Biophysics, National Research Council (CNR) Unit at Trento, 38123 Povo, Italy; 2Biomedical Center (BMC), Department of Physiological Genomics, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany; 3Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, 82152 Planegg-Martinsried, Germany; 4SYNERGY, Excellence Cluster of Systems Neurology, Biomedical Center, Ludwig-Maximilians-University, 82152 Planegg-Martinsried, Germany Corresponding authors: magdalena.goetzbmc.med.lmu.de, rschieweckfbk.eu Abstract

Cell diversification is at the base of increasing multicellular organism complexity in phylogeny achieved during ontogeny. However, there are also functions common to all cells, such as cell division, cell migration, translation, endocytosis, exocytosis, etc. Here we revisit the organelles involved in such common functions, reviewing recent evidence of unexpected differences of proteins at these organelles. For instance, centrosomes or mitochondria differ significantly in their protein composition in different, sometimes closely related, cell types. This has relevance for development and disease. Particularly striking is the high amount and diversity of RNA-binding proteins at these and other organelles, which brings us to review the evidence for RNA at different organelles and suborganelles. We include a discussion about (sub)organelles involved in translation, such as the nucleolus and ribosomes, for which unexpected cell type-specific diversity has also been reported. We propose here that the heterogeneity of these organelles and compartments represents a novel mechanism for regulating cell diversity. One reason is that protein functions can be multiplied by their different contributions in distinct organelles, as also exemplified by proteins with moonlighting function. The specialized organelles still perform pan-cellular functions but in a cell type-specific mode, as discussed here for centrosomes, mitochondria, vesicles, and other organelles. These can serve as regulatory hubs for the storage and transport of specific and functionally important regulators. In this way, they can control cell differentiation, plasticity, and survival. We further include examples highlighting the relevance for disease and propose to examine organelles in many more cell types for their possible differences with functional relevance.