Trends in Cell Biology最新文献

The glycan makeup of membrane glycoproteins and glycosphingolipids at the cell surface is traditionally viewed as mature and static. Recent findings challenge this view, showing that selective glycan remodeling can redirect membrane glycoproteins back to the Golgi for another go. In this review we discuss the glycosylation processes in cells, with a focus on the terminal glycan chains on proteins and lipids that are capped by sialic acid sugars, and that engage the glycan-binding proteins of the galectin family. We highlight new studies demonstrating that growth factors trigger the removal of sialic acid by endogenous neuraminidases at the cell surface, leading to glycolipid-lectin driven endocytosis and retrograde traffic to the Golgi. This molecular circuit, termed the GlycoSwitch, introduces new perspectives on glycan-mediated regulation of cellular functions.

The Hippo signaling pathway has a critical role in regulating tissue growth, development, and tumor suppression. Mutations in NF2, which encodes the tumor suppressor Merlin, disrupt Hippo signaling, causing aberrant activation of YAP/TAZ and contributing to diseases, such as cancer and developmental disorders. Recent studies have identified novel mechanisms by which biomolecular condensation and phosphoinositides regulate Merlin function in Hippo signaling. Furthermore, NF2 deficiency sensitizes cells to ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. In this review, I highlight the emerging roles of Merlin-YAP signaling in physiology and disease, focusing on its regulation through biomolecular condensates, its contribution to development and ferroptosis, and its implications for therapeutic interventions.

Lysosomes degrade damaged or unwanted cell/tissue components and recycle their building blocks through small-molecule transporters of the lysosomal membrane. They also act as signaling hubs that sense and signal internal cues, such as amino acids, to coordinate cell responses. Recently, the activity of several lysosomal metabolite transporters has been elucidated, bringing new insights into lysosomal functions. Cell biological and structural studies of lysosomal transporters have also highlighted their roles in recruiting signaling complexes to lysosomes and delineated how their substrates gate such hybrid transporter/receptor, or 'transceptor', function. In this review, we summarize recent progress in our understanding of lysosomal transporters, with a focus on the export of lysosomal degradation intermediates, the existence of lysosomal amino acid shuttles that regulate the redox state and pH of the lysosomal lumen, and the role of lysosomal transceptors in nutrient and immune signaling.

The canonical role of the ribosome is to translate the genetic code into functional proteins. Recent discoveries, however, redefine the eukaryotic ribosome, as a regulatory hub, that senses cellular cues and transmits signals to downstream pathways. The P-stalk, an integral component of the ribosomal GTPase-associated center, once viewed as translational supporter, is now emerging as a key regulatory ribosomal module. It has recently been recognized as an activator of the integrated stress response, reshaping the Gcn1/Gcn20→Gcn2 axis into the new Gcn1/Gcn20/P-stalk→Gcn2 order. The P-stalk's structural plasticity allows also the ribosome to rewire gene expression in response to cellular demands, including cytokine response. In this review, an updated functional portrait of the P-stalk is presented, encompassing both ribosome-dependent and -independent activities.

Defects in ribosomal machinery cause ribosomopathies such as Diamond Blackfan anemia, classically linked to impaired protein synthesis. However, emerging evidence places mitochondrial dysfunction as a critical downstream consequence of ribosomal insufficiency. Thus, is impaired energy metabolism, rather than translation alone, a key driver of ribosomopathies such as Diamond Blackfan anemia? This insight could reframe our understanding of disease mechanisms and could identify metabolic pathways as promising therapeutic targets.

Virus-associated cancers, which account for ~15-20% of the global cancer burden, arise from infections with human oncoviruses. These viruses drive malignant transformation through diverse mechanisms but share common oncogenic features, including reprogramming host membrane signaling and trafficking. Such processes are tightly regulated by phosphoinositides (PPIn), essential organizers of membrane dynamics and signal transduction implicated in cancer development and progression. Oncoviruses exploit host PPIn metabolism to facilitate their replication and persistence, often leading to its dysregulation. In turn, this disruption can activate oncogenic signaling pathways that promote malignant transformation. In this review, we summarize how oncoviruses manipulate PPIn metabolism to sustain their life cycle and drive long-term interactions with host cells, ultimately contributing to tumorigenesis.

The phase separation of the cargo receptor sequestome-1/p62 (SQSTM1/p62) is a critical mechanism for assembling signaling complexes in autophagy. During this process, p62 undergoes phase separation upon binding to polyubiquitin chains, concentrating ubiquitinated substrates within p62 droplets. These droplets further gather membrane sources and core autophagy machineries to facilitate autophagosome formation. The dynamics of p62 droplets are finely tuned in response to autophagy signals triggered by cellular stresses. Recent studies have revealed new regulatory mechanisms that highlight the significance of p62 phase separation in regulating autophagy. This review summarizes and discusses the molecular mechanisms of p62 phase separation and its roles in autophagy, with particular emphasis on the regulation of p62 droplets and their interaction modes with autophagic membranes.

The dynamic turnover of actin filaments drives the morphogenesis and migration of all eukaryotic cells. This review summarizes recent insights into the molecular mechanisms of actin polymerization and disassembly obtained through high-resolution structures of actin filament assemblies. We first describe how, upon polymerization, actin subunits age within the filament through changes in their associated adenine nucleotide. We then focus on the molecular basis of actin filament growth at the barbed end and how this process is modulated by core regulators such as profilin, formin, and capping protein (CP). Finally, the mechanisms underlying actin filament pointed-end depolymerization through disassembly factors cofilin/cyclase-associated protein (CAP) or DNase I are discussed. These findings contribute to a structural understanding of how actin filament dynamics are regulated in a complex cellular environment.

In recent years, studies have reported the presence of mitochondrial DNA (mtDNA) in the cytosol. However, a certain number of publications on the mechanisms of mtDNA release contain uncertainties. mtDNA is located in the mitochondrial matrix and cannot be released through the same pathways as intermembrane space proteins. This forum article aims to examine the assumptions and elucidate the processes underlying this phenomenon.

Metabolic pathways and DNA replication are both adaptable and essential for early development and cancer progression. While each process is well understood individually, the mechanisms coordinating them are just beginning to emerge. Nucleotide biosynthesis serves as a crucial link, with fluctuating nucleotide pools leading to imbalanced deoxyribonucleotide (dNTP) and increased ribonucleotide (rNTP) levels, impairing DNA synthesis and triggering replication stress; ultimately driving developmental disorders and cancer. To counter these challenges, the replisome - the core machinery of DNA replication - continuously adjusts its architecture and speed in response to physiological changes, including nucleotide fluctuations. This review outlines recent insights into how the replisome aligns its function with metabolic changes in nucleotide levels and explores emerging links between metabolism and genome stability, and their roles in development and disease.