Biology subjects

Yang, T. T.

Publications and source records attributed to Yang, T. T..

7 recordsLinked to original sources

bioRxiv2025

Centriole biogenesis is seeded by CEP152-CEP63-PCNT aggregates propagating outside the centriole through the Alstrom syndrome protein ALMS1

Biogenesis of subcellular structures like centrioles is viewed as a physical transformation wherein elementary constituents form order without preexisting templates. Centrioles grow with precision from a composite scaffold known as the cartwheel, which is thought to self-assemble without templates and disassemble following centriole growth; however, the mechanism governing cartwheel assembly-disassembly dynamics remains obscure. Here, we identify ALMS1, a disease-linked, intrinsically disordered protein (IDP), as an external mediator of cartwheel dynamics that causes a seed for cartwheel--and thus centriole--formation without itself incorporating into the seed structure. The cartwheel seed (CS), characterized as a dense composite of CEP152/CEP63 protein complexes, forms in interphase and adopts a nanoscale, concentric ring from which the cartwheel grows. Upon mitotic entry, CSs recruit ALMS1 while disassembling into constituents associating with ALMS1 in proximity, correlating with cartwheel assembly-disassembly cycles. Hypomorph, disease-linked ALMS1 mutations trigger cartwheel expansion and shedding by its own grown procentriole, in turn forming ectopic centrioles, leading to perpetual reciprocal amplification. Without ALMS1, CS formation fails, negating centriole biogenesis, whereas reintroducing ALMS1 initializes biogenesis anew, creating diverse yet heritable architectures that evolve through selection, instead of generating a single canonical form. These results suggest that centriole biogenesis is grounded on adaptable transformation cues extrinsic to its constituents, propagating via IDP-mediated CS assembly-disassembly cycles, a process we conjecture involves memory.

cell biology↗

bioRxiv2025

SSNA1 organizes the distal luminal centriolar network and promotes ciliogenesis without microtubule association

The distal lumen of the centriole plays a critical role in ciliogenesis, yet the molecular composition, spatial organization, and targeting hierarchy of distal luminal proteins remain poorly understood. In this study, we identify Sjogrens syndrome nuclear autoantigen 1 (SSNA1) as a bona fide centriolar protein and a key regulator of ciliogenesis in mammalian cells. Using our newly developed knockout (KO)-validated antibody, we show that, contrary to previous reports, SSNA1 does not reside in the nucleus, midbody, or ciliary axoneme. Instead, super-resolution imaging combined with expansion microscopy (ExM) reveals that SSNA1 localizes to the distal lumen of centrioles and the basal bodies of both primary and motile cilia, where it is arranged in a ring-like configuration with 9-fold symmetry and apart from centriolar microtubules. Molecular dissection using tag-free SSNA1, its oligomerization-deficient mutants, and microtubule co-pelleting assays further demonstrates that SSNA1, previously described as a microtubule nucleator, stabilizer, and branching factor, does not bind microtubules in vitro. Interactor screening and KO analysis unveil a hierarchical targeting network involving a C2CD3-SSNA1-LRRCC1 axis in the distal lumen. Functional characterization indicates that although dispensable for cell division, overall centriole organization and duplication, SSNA1 promotes cilia assembly by facilitating CP110 removal. Our findings redefine the physiological role of SSNA1 as part of the distal luminal module contributing to ciliogenesis and provide new insights into the molecular architecture and functional relevance of the distal centriolar lumen. SignificanceCentrioles template the assembly of cilia and flagella, whose dysfunction causes human diseases known as ciliopathies. Key centriolar structures - the cartwheel in the proximal lumen, the inner scaffold in the central lumen, and the distal and subdistal appendages outside the distal lumen - have been extensively characterized. However, the molecular organization and functional relevance of the distal lumen remain largely unexplored. Here, we identify SSNA1 as a novel centriolar component at the distal lumen and an essential regulator of ciliogenesis. Our work challenges the long-held view of SSNA1 as a microtubule-associated protein and provides new insights into the architecture, interaction network, targeting hierarchy, and function of the distal centriolar lumen, exemplifying how it modulates centriolar organization and drives ciliogenesis.

cell biology↗

bioRxiv2025

Increased rates of hybridization in swordtail fish are associated with water pollution

Understanding the nature of reproductive barriers separating species is a fundamental goal of evolutionary biology. Such barriers may be environmentally sensitive, and recent research has documented an increasing number of cases where anthropogenic environmental disturbance is associated with hybridization. However, few studies have been able to quantify and compare potential environmental mechanisms connecting anthropogenic disturbance to hybridization. Here, we combine genomic and environmental surveys to explore the loss of reproductive isolation between Xiphophorus malinche and X. birchmanni, fishes whose riverine habitat in montane Mexico is increasingly impacted by human-mediated disturbance. By inferring genome-wide ancestry in thousands of fish, we characterize the landscape of hybridization between these sister species in four drainages. Ancestry structure varies across streams from stable coexistence to clinal hybrid zones, hinting that hybridization dynamics in this system may be environmentally dependent. In one stream, sites upstream of an urbanized area host distinct sympatric ancestry clusters, while downstream sites collapse into a hybrid swarm. By sequencing mothers and embryos, we show that assortative mating is weakened downstream of this urbanized area. We hypothesize that the downstream hybrid swarm is driven by chemical disruption of olfaction that impacts mating preferences. Water chemistry measurements show significant changes across the urbanized area, including in parameters known to disrupt fish olfaction and mating. We identify alterations of the olfactory epithelium between sites upstream and downstream of the urbanized area consistent with differential effects of water quality. Taken together, our work illuminates potential mechanisms linking anthropogenic disturbance to the breakdown of reproductive isolation.

evolutionary biology↗

bioRxiv2022

Single-molecule localization microscopy reveals the ultrastructural root constitution of distal appendages in expanded mammalian centrioles

Distal appendages (DAPs) are vital in cilia formation, mediating vesicular and ciliary docking to the plasma membrane during early ciliogenesis. Although numerous DAP proteins arranging a nine-fold symmetry have been studied using superresolution microscopy analyses, the extensive ultrastructural understanding of the DAP root structure developing from the centriole wall remains elusive owing to insufficient resolution. Here, we proposed a pragmatic imaging strategy for two-color single-molecule localization microscopy of swellable mammalian DAP proteins. Importantly, our imaging workflow enables us to push the resolution limit of a light microscope well close to an electron microscopy level, thus achieving an unprecedented {lambda}/200 mapping precision inside intact cells. Upon this workflow, we unravel the ultraresolved higher-order protein complexes of the core DAP. Intriguingly, C2CD3, microtubule triplet, and ODF2 jointly constitute the spatial basis of DAP, suggesting a unique configuration of the DAP assembly. Moreover, our results show that the distal-layered ODF2 labeled at the N- and C-terminus construct a fastening unit encircling the microtubule triplets. Together, we develop an organelle-based drift correction protocol and a two-color solution with minimum crosstalk, allowing a robust localization microscopy imaging of expanded cellular structures deep into the gel-specimen composites.

biophysics↗

bioRxiv2020

Mitochondrial ATP Synthase Trafficking along Microtubules to Cell Surface Depends on KIF5B and DRP1

Ectopic adenosine triphosphate (eATP) synthase, located on the cell surface instead of the mitochondrial inner membrane, has been discovered to be a novel target for the treatment of various types of cancer. However, the mechanism of eATP synthase trafficking toward the cell surface remains unclear. In this study, we used an integrative approach incorporating multiomics, super-resolution imaging, real-time live-cell tracing, and various functional analyses to derive a transport model of eATP synthase from the mitochondria to the plasma membrane in cancer cells. We determined that the ATP synthase complex is first assembled in the mitochondria and subsequently delivered to the cell surface through the microtubule-mediated mitochondrial transport pathway. We also found that dynamin-related protein 1 (DRP1) enhances mitochondrial fission and subsequently associates with microtubule motor protein kinesin family member 5B (KIF5B) to promote the subcellular transportation of eATP synthase. Consequently, our work provides a blueprint for eATP synthase trafficking from the mitochondria toward the cell surface.

systems biology↗

bioRxiv2018

Cortisol Predicts Antidepressant Treatment Outcome, Memory Improvement, and Brain Response to Negative Emotions: The Importance of Aging

BackgroundStudies testing the relationship between cortisol levels, depression, and antidepressant treatment response have yielded divergent results suggesting the possibility of moderators of a cortisol effect. Several studies indicate that age may moderate the relationship between cortisol and psychopathology. In patients with Major Depressive Disorder (MDD), we studied the interactive effects of age and cortisol on predicting diagnostic status, improvement in mood and memory function with antidepressant treatment, and brain response to negative emotional stimuli.\n\nMethods66 unmedicated patients with MDD and 75 matched healthy controls had serum assayed at pre-treatment baseline for cortisol. Logistic regression was used to determine an association of age, cortisol and their interaction with MDD diagnosis. Thirty-four of the MDD participants (age range: 19-65 years; median: 36) underwent treatment with a selective serotonin reuptake inhibitor (SSRl) for 8 weeks. Clinician and self-ratings of depression symptoms, as well as tests of verbal and visual delayed recall were obtained at baseline and post treatment. Moderation analyses determined the effect of age on the relationship between baseline cortisol and treatment outcome. A separate sample of 8 MDD participants prospectively underwent fMRI neuroimaging and cortisol collection while viewing negative emotional faces.\n\nResultsAge moderated the effects of cortisol on predicting MDD diagnosis (p<.05), treatment-associated reduction of depression symptoms (p<.001), improvement of delayed recall (p<.001), and baseline brain response to negative emotions (p<.05, whole brain corrected). Modeling the Age X Cortisol interaction suggested that for the participants below the median age of our sample, lower cortisol levels predicted a lower rate of MDD diagnosis, higher antidepressant effects and decreased brain reactivity in emotion regulation regions such as the anterior cingulate gyrus. On the contrary, in those above the median sample age, lower cortisol predicted a higher rate of MDD, less improvement in depression symptoms and memory performance, and more brain reactivity in the anterior cingulate.\n\nConclusionsOur results indicate that age moderates the relationship between peripheral cortisol levels and (1) MDD diagnosis, (2) brain reactivity to emotional stimuli, and (3) antidepressant-associated improvement in depression and memory symptoms. These results indicate that previous disparities in the literature linking peripheral cortisol levels with depression characteristics and treatment response may critically relate, at least in part, to the age of the patients studied.

physiology↗

bioRxiv2017

Architecture of mammalian centriole distal appendages accommodates distinct blade and matrix functional elements

Distal appendages (DAPs) are nanoscale, pinwheel-like structures protruding from the distal end of the centriole that mediate membrane docking during ciliogenesis, marking the cilia base around the ciliary gate. Here, we determined a superresolved multiplex of 16 centriole-distal-end components. Surprisingly, rather than pinwheels, intact DAPs exhibit a cone-shaped architecture with components filling the space between each pinwheel blade, a new structural element we termed the distal appendage matrix (DAM). Specifically, CEP83, CEP89, SCLT1, and CEP164 form the backbone of pinwheel blades, with CEP83 confined at the root and CEP164 extending to the tip near the membrane-docking site. By contrast, FBF1 marks the distal end of the DAM near the ciliary membrane. Strikingly, unlike CEP164 which is essential for ciliogenesis, FBF1 is required for ciliary gating of transmembrane proteins, revealing DAPs as an essential component of the ciliary gate. Our findings redefine both the structure and function of DAPs.

cell biology↗