Annual review of biochemistry最新文献

Metabolism and gene regulation are vital processes that need to be tightly coordinated to maintain homeostasis or to enable growth and development. Recent research has begun to reveal the surprisingly interlaced relationship between metabolism and gene expression control. Because key metabolites are cofactors or cosubstrates of chromatin-modifying enzymes, changes in their concentrations can modulate chromatin states and gene expression. Additionally, an increasing number of key metabolic enzymes are found to directly regulate chromatin and transcription in response to changes in metabolic state. These include enzymes that fuel chromatin-associated metabolism and moonlighting enzymes that function as transcription factors, independent of their enzymatic activity. Conversely, accumulating evidence suggests that chromatin itself serves key metabolic functions, independent of transcriptional regulation. Here, we discuss the bidirectional interface between metabolism and chromatin and its corruption in cancer cells.

Viruses must egress from the cells in which they have replicated to spread and propagate. Historically, viruses have been classified into enveloped and nonenveloped forms: Enveloped viruses exploit cellular membrane-trafficking pathways to egress while maintaining cell integrity, and nonenveloped viruses, i.e., those lacking a membrane around their capsids, lytically egress. Here, we make the compelling case that all animal and plant and many archaeal and bacterial viruses egress through nonlytic pathways. Most of these nonlytic pathways can be separated into those that enable viruses to spread without leaving the confines of cell bodies and those that traffic them to the extracellular space in enveloped membrane-bound forms. Nonlytic egress pathways bestow viruses with distinct transmission advantages including high multiplicity of infection, quality control over transmitting infectious units, and evasion of innate and adaptive antiviral immune defense mechanisms.

Discovered in 1993, inositol pyrophosphates are evolutionarily conserved signaling metabolites whose versatile modes of action are being increasingly appreciated. These include their emerging roles as energy regulators, phosphodonors, steric/allosteric regulators, and G protein-coupled receptor messengers. Through studying enzymes that metabolize inositol pyrophosphates, progress has also been made in elucidating the various cellular and physiological functions of these pyrophosphate-containing, energetic molecules. The two main forms of inositol pyrophosphates, 5-IP₇ and IP₈, synthesized respectively by inositol-hexakisphosphate kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks), regulate phosphate homeostasis, ATP synthesis, and several other metabolic processes ranging from insulin secretion to cellular energy utilization. Here, we review the current understanding of the catalytic and regulatory mechanisms of IP6Ks and PPIP5Ks, as well as their counteracting phosphatases. We also highlight the genetic and cellular evidence implicating inositol pyrophosphates as essential mediators of mammalian metabolic homeostasis.

The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo-electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system.

RAF family protein kinases are a key node in the RAS/RAF/MAP kinase pathway, the signaling cascade that controls cellular proliferation, differentiation, and survival in response to engagement of growth factor receptors on the cell surface. Over the past few years, structural and biochemical studies have provided new understanding of RAF autoregulation, RAF activation by RAS and the SHOC2 phosphatase complex, and RAF engagement with HSP90-CDC37 chaperone complexes. These studies have important implications for pharmacologic targeting of the pathway. They reveal RAF in distinct regulatory states and show that the functional RAF switch is an integrated complex of RAF with its substrate (MEK) and a 14-3-3 dimer. Here we review these advances, placing them in the context of decades of investigation of RAF regulation. We explore the insights they provide into aberrant activation of the pathway in cancer and RASopathies (developmental syndromes caused by germline mutations in components of the pathway).

Writing a career retrospective for this prestigious series is a huge challenge. Is my story really of that much interest? One thing that is different about my life in science is the heavy influence of the turmoil of the past century. Born in the US, raised in East Germany, and returning to the US relatively late in life, I experienced research under both suboptimal and privileged conditions. My scientific story, like the political winds that blew me from one continent to the next, involved shifts into different fields. For advice to young scientists, I would suggest: Don't be afraid to start something new, it pays to be persistent, and science is a passion. In addition to telling my own story, this article also provides the opportunity to express my gratitude to my trainees and colleagues and to convey my conviction that we have the best job on earth.

During the last ten years, developments in cryo-electron microscopy have transformed our understanding of eukaryotic ribosome assembly. As a result, the field has advanced from a list of the vast array of ribosome assembly factors toward an emerging molecular movie in which individual frames are represented by structures of stable ribosome assembly intermediates with complementary biochemical and genetic data. In this review, we discuss the mechanisms driving the assembly of yeast and human small and large ribosomal subunits. A particular emphasis is placed on the most recent findings that illustrate key concepts of ribosome assembly, such as folding of preribosomal RNA, the enforced chronology of assembly, enzyme-mediated irreversible transitions, and proofreading of preribosomal particles.

Cellular quality control systems sense and mediate homeostatic responses to prevent the buildup of aberrant macromolecules, which arise from errors during biosynthesis, damage by environmental insults, or imbalances in enzymatic and metabolic activity. Lipids are structurally diverse macromolecules that have many important cellular functions, ranging from structural roles in membranes to functions as signaling and energy-storage molecules. As with other macromolecules, lipids can be damaged (e.g., oxidized), and cells require quality control systems to ensure that nonfunctional and potentially toxic lipids do not accumulate. Ferroptosis is a form of cell death that results from the failure of lipid quality control and the consequent accumulation of oxidatively damaged phospholipids. In this review, we describe a framework for lipid quality control, using ferroptosis as an illustrative example to highlight concepts related to lipid damage, membrane remodeling, and suppression or detoxification of lipid damage via preemptive and damage-repair lipid quality control pathways.

Racial stress and racial trauma refer to psychological, physiological, and behavioral responses to race-based threats and discriminatory experiences. This article reviews the evidence base regarding techniques for coping with racial stress and trauma. These techniques include self-care, self-compassion, social support, mindfulness, cognitive restructuring, cognitive defusion, identity-affirming practices and development of racial/ethnic identity, expressive writing, social action and activism, and psychedelics. These strategies have shown the potential to mitigate psychological symptoms and foster a sense of empowerment among individuals affected by racial stress and trauma. While the ultimate goal should undoubtedly be to address the root cause of racism, it is imperative to acknowledge that until then, implementing these strategies can effectively provide much-needed support for individuals affected by racism.

Alcohol's link with sexuality is long-standing and prominent. While research continues to document robust associations between drinking and sexual behavior, scientific attention now centers primarily on evaluating mechanisms and attendant theoretical frameworks to advance our understanding of how alcohol exerts a causal impact. We describe four domains with reliable evidence of alcohol effects: sexualized social perceptions, sexual arousal, sexual risk taking, and sexual assault. We consider three contextual frames: distal factors associated with encountering opportunities for alcohol-involved sex, proximal factors associated with alcohol's acute effects, and distal-proximal interactions. We then examine the empirical support for mechanisms embedded within four theoretical frameworks: alcohol disinhibition, alcohol expectancy, alcohol myopia, and emotion regulation. Support for disinhibition mechanisms is evident with sexual arousal only. Expectancy and myopia mechanisms enjoy support across domains and make up bases for integrative expectancy-myopia causal explanations. Emotion regulation mechanisms evidence preliminary support in risk taking and sexual assault. Implications and future directions are considered.