Biological Chemistry最新文献

Eukaryotic life is defined by the presence of organelles. Organelles, in turn, were classically defined as specialized membrane-bound compartments composed of a unique set of macromolecules which support specific functions. Over the last few decades, a concerted effort into uncovering which components are present in each organelle has shaped our view of cell biology. However, despite some organelles already being visualized over 100 years ago, we are still discovering new organelle residents. Furthermore, our concept of both 'organelles' and 'compartmentalization' has evolved together with our deepening understanding in a number of fields. These include: organelle substructure and organization; the network of contact sites which interconnects all organelles; and membraneless organelles and phase-separated condensates. This review explores how image- and mass spectrometry-based methods can be used to understand the spectrum of where components are localized: from complexes, to subdomains, and whole organelles. The components we mainly focus on are proteins of the mitochondria and secretory pathway organelles.

The literature on the lipid droplet organization (LDO) proteins Ldo16 and Ldo45 reads like a guided tour through the lipid droplet life cycle. Both yeast Ldo16/45 and their metazoan counterparts, the LDAF1/promethin proteins, were originally identified based on their connection to the lipodystrophy protein seipin, a key player in lipid droplet biogenesis. Mechanistic follow-up studies support a role of LDAF1/LDO as conserved integral component of the seipin lipid droplet biogenesis complex. However, at the same time, additional LDO functions beyond lipid droplet formation were identified in yeast. Together with Vac8, Ldo16/45 act as tethers for formation of vacuole lipid droplet (vCLIP) contact sites, structures that are crucial for lipid droplet breakdown via microautophagy during glucose starvation. Ldo45 additionally recruits the lipid transfer protein Pdr16 to vCLIP. Furthermore, Ldo16 was identified as a central player in the process of actomyosin-based lipid droplet motility, by acting as a receptor for the myosin adaptor protein Ldm1. Based on these findings, we suggest an overarching molecular role of the LDO proteins as multifunctional lipid droplet surface receptors that are optimized to coordinate the different aspects of the lipid droplet life cycle through an interplay with different effector proteins.

The diverse, and sometimes opposing, roles of mitochondria require sophisticated organizational and regulatory strategies. This review examines emerging evidence that mitochondria can solve this challenge through functional specialization - adopting distinct bioenergetic and metabolic programs based on location, contacts, and cellular conditions. We discuss both established principles and recent technological breakthroughs that reveal this hidden complexity. Ongoing advances promise to move the field from describing mitochondrial diversity to uncovering its regulatory mechanisms and therapeutic potential.

The phylum Euglenozoa, within the Eukaryote domain, includes diverse protists such as the medically significant kinetoplastids, characterized by their unique kinetoplast DNA. Both kinetoplastids and their sister class Diplonemea possess glycosomes - specialized microbodies that compartmentalize glycolysis and other metabolic pathways. Glycosomes likely evolved in a common ancestor of kinetoplastid and diplonemids, conferring metabolic flexibility and reducing cellular toxicity. These organelles are essential for parasite survival and thus, represent promising drug targets for treating kinetoplastid diseases. While the basic principles of peroxisome and glycosome biogenesis are conserved, distinct features in glycosome biogenesis machinery and a lower level of sequence conservation enables pathogen specific drug design for developing new therapies. This review summarizes our current knowledge on glycosome biogenesis, recent advances, and therapeutic potential for treating trypanosomatid infections.

Dendritic spines are the postsynaptic compartment of most excitatory synapses in the vertebrate brain. Their morphology is defined by a complex actin scaffold consisting of branched and unbranched actin filaments (F-actin), which constitute the major structural component of dendritic spines. During brain development, dendritic spines arise from dendritic filopodia, motile finger-like dendritic protrusions, whose morphology is also defined by an actin scaffold. The organization of the actin scaffold as well as its dynamic behavior in both dendritic filopodia and dendritic spines requires the coordinated activity of actin binding proteins (ABP) that promote either assembly or disassembly of F-actin. Studies of the past two decades identified a number of ABP and upstream regulatory pathways that control the morphology of dendritic spines as well as their morphological changes associated with synaptic plasticity, the cellular basis for learning and memory. Instead, much less is known about actin regulatory mechanisms that control the formation and elongation of dendritic filopodia or the structural changes associated with their transition into dendritic spines. This review article highlights recent advances in the field by summarizing and discussing studies of the past few years that provided exciting novel insights into the molecular machinery that governs dendritic filopodia initiation and their maturation into dendritic spines.

The small protein family of VAMP-associated proteins (VAPs) have the unique position in cell biology as intracellular signposts for the Endoplasmic Reticulum (ER). VAP is recognised by a wide range of other proteins that use it to target the ER, either simply being recruited from the cytoplasm, or being recruited from separate organelles. The latter process makes VAP a component of many bridges between the ER and other compartments at membrane contact sites. The fundamental observations that identify VAP as the ER signpost have largely remained unchanged for over two decades. This review will describe how increased understanding of the special role of VAP in recent years has led to new discoveries: what constitutes the VAP family, how proteins bind to VAP, and which cellular functions connect to the ER using VAP. It will also describe the pitfalls that have led to difficulties determining how some proteins bind VAP and suggest some possibilities for future research.

The rapid spread of bacterial resistance to antibiotics necessitates the development of innovative strategies to enhance their efficacy. One promising approach is incorporating antimicrobial peptides (AMPs) to synergize antibiotics. Herein, we introduce pH-responsive nanoplexes of plant AMP and sodium alginate (Na-Alg) for the co-delivery of AMP and Vancomycin (VCM) against resistant bacteria. The optimal nanoplexes (VCM-Na-Alg/AMP) were characterized, revealing a particle size, polydispersity index, zeta potential, encapsulation efficiency, and loading capacity of 159.5 ± 1.150 nm, 0.149 ± 0.018, -23.1 ± 0.1 mV, 82.34 ± 0.07 %, and 24.03 ± 0.10 % w/w, respectively. The nanoplexes exhibited pH-dependent changes in size and accelerated VCM release at acidic pH. In vitro antibacterial studies demonstrated a 2-fold enhanced activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) and a 5-fold greater MRSA biofilm eradication, compared to bare VCM. Furthermore, the in vivo antibacterial activity evaluated on a mice model of MRSA systemic infection demonstrated that the nanoplexes reduced MRSA burden by 5-fold in kidneys and 4-fold in liver and blood. The nanoplexes also exhibited reduced inflammation and improved tissue integrity in the treated subjects. These findings present VCM-Na-Alg/AMP as a novel strategy to augment the efficacy of antibiotics against resistant bacteria.

Polyamines are ubiquitous and essential for cellular physiology, yet their metabolic pathways and functions remain only partially understood. Polyamine oxidases (PAO) are key to elucidating their physiological roles. In the methylotrophic yeast Ogataea parapolymorpha, we identified three putative PAO-encoding genes. Biochemical characterization showed that two of them function as PAOs, whereas the third has unknown substrate specificity. In contrast to previously studied yeasts, including Saccharomyces cerevisiae, which contain only a single PAO, O. parapolymorpha harbors multiple and functionally distinct PAOs. These findings highlight an unexpected diversification of polyamine catabolism in yeast and suggest previously unrecognized roles of PAOs in cellular physiology.