Annual Review of Cell and Developmental Biology - Volume 33, 2017

In eukaryotes, the synthesis and uptake of sterols undergo stringent multivalent regulation. Both individual enzymes and transcriptional networks are controlled to meet changing needs of the many sterol pathway products. Regulation is tailored by evolution to match regulatory constraints, which can be very different in distinct species. Nevertheless, a broadly conserved feature of many aspects of sterol regulation is employment of proteostasis mechanisms to bring about control of individual proteins. Proteostasis is the set of processes that maintain homeostasis of a dynamic proteome. Proteostasis includes protein quality control pathways for the detection, and then the correction or destruction, of the many misfolded proteins that arise as an unavoidable feature of protein-based life. Protein quality control displays not only the remarkable breadth needed to manage the wide variety of client molecules, but also extreme specificity toward the misfolded variants of a given protein. These features are amenable to evolutionary usurpation as a means to regulate proteins, and this approach has been used in sterol regulation. We describe both well-trod and less familiar versions of the interface between proteostasis and sterol regulation and suggest some underlying ideas with broad biological and clinical applicability.

Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids for energy or membrane synthesis and act as hubs for metabolic processes. Cells generate LDs de novo, converting cells to emulsions with LDs constituting the dispersed oil phase in the aqueous cytoplasm. Here we review our current view of LD biogenesis. We present a model of LD formation from the ER in distinct steps and highlight the biology of proteins that govern this biophysical process. Areas of incomplete knowledge are identified, as are connections with physiology and diseases linked to alterations in LD biology.

A majority of T cells bearing the αβ T cell receptor (TCR) are specific for peptides bound to polymorphic classical major histocompatibility complex (MHC) molecules. Smaller subsets of T cells are reactive toward various nonpeptidic ligands associated with nonpolymorphic MHC class-Ib (MHC-Ib) molecules. These cells have been termed unconventional for decades, even though only the composite antigen is different from the one seen by classical T cells. Herein, we discuss the identity of these particular T cells in light of the coevolution of their TCR and MHC-Ib restricting elements. We examine their original thymic development: selection on hematopoietic cells leading to the acquisition of an original differentiation program. Most of these cells acquire memory cell features during thymic maturation and exhibit unique patterns of migration into peripheral nonlymphoid tissues to become tissue resident. Thus, these cells are termed preset T cells, as they also display a variety of effector functions. They may act as microbial or danger sentinels, fight microbes, or regulate tissue homeostasis.

The recent flood of single-cell data not only boosts our knowledge of cells and cell types, but also provides new insight into development and evolution from a cellular perspective. For example, assaying the genomes of multiple cells during development reveals developmental lineage trees—the kinship lineage—whereas cellular transcriptomes inform us about the regulatory state of cells and their gradual restriction in potency—the Waddington lineage. Beyond that, the comparison of single-cell data across species allows evolutionary changes to be tracked at all stages of development from the zygote, via different kinds of stem cells, to the differentiating cells. We discuss recent insights into the evolution of stem cells and initial attempts to reconstruct the evolutionary cell type tree of the mammalian forebrain, for example, by the comparative analysis of neuron types in the mesencephalic floor. These studies illustrate the immense potential of single-cell genomics to open up a new era in developmental and evolutionary research.

Our understanding of the detailed molecular mechanisms underpinning adaptation is still poor. One example for which mechanistic understanding of regulation has converged with studies of life history variation is Arabidopsis thaliana FLOWERING LOCUS C (FLC). FLC determines the need for plants to overwinter and their ability to respond to prolonged cold in a process termed vernalization. This review highlights how molecular analysis of vernalization pathways has revealed important insight into antisense-mediated chromatin silencing mechanisms that regulate FLC. In turn, such insight has enabled molecular dissection of the diversity in vernalization across natural populations of A. thaliana. Changes in both cotranscriptional regulation and epigenetic silencing of FLC are caused by noncoding polymorphisms at FLC. The FLC locus is therefore providing important concepts for how noncoding transcription and chromatin regulation influence gene expression and how these mechanisms can vary to underpin adaptation in natural populations.

Both sex (i.e., biological differences) and gender (i.e., social or cultural influences) impact vaccine acceptance, responses, and outcomes. Clinical data illustrate that among children, young adults, and aged individuals, males and females differ in vaccine-induced immune responses, adverse events, and protection. Although males are more likely to receive vaccines, following vaccination, females typically develop higher antibody responses and report more adverse effects of vaccination than do males. Human, nonhuman animal, and in vitro studies reveal numerous immunological, genetic, hormonal, and environmental factors that differ between males and females and contribute to sex- and gender-specific vaccine responses and outcomes. Herein, we address the impact of sex and gender variables that should be considered in preclinical and clinical studies of vaccines.