Biology subjects

Weisman, L. S.

Publications and source records attributed to Weisman, L. S..

6 recordsLinked to original sources

bioRxiv2026

A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.

cancer biology↗

bioRxiv2025

Cargo adaptors use a handhold mechanism to engage with myosin V for organelle transport

Myo2, a myosin V motor, is essential for organelle transport in budding yeast. Its attachment to and detachment from cargo are mediated by adaptor molecules. Vac17, a vacuole-specific adaptor, links Myo2 to Vac8 on the vacuole membrane, and plays a key role in the formation and dissociation of the Myo2-Vac17-Vac8 complex. Using genetics, cryo-electron microscopy and structure prediction, we find that Vac17 interacts with Myo2 through two distinct sites rather than a single interface. Similarly, the peroxisome adapter Inp2 engages two separate regions of Myo2, one of which overlaps with Vac17. These findings support a "handhold" model, in which cargo adaptors occupy multiple sites on the Myo2 tail, enhancing motor-cargo interactions and likely providing additional regulatory control over motor recruitment. SummaryThis study provides insights into how cargo adaptors bind myosin V. Genetics, cell-based assays, cryo-EM, and AlphaFold, reveal that the vacuole-specific adaptor uses a handhold mechanism to attach to two areas on the myosin V tail. Moreover, evidence is presented that other adaptors use a similar strategy.

cell biology↗

bioRxiv2024

A non-canonical CDK, Pho85 regulates the restart of the cell-cycle following stress

Environmental stress induces an arrest of the cell cycle. Thus, release from this arrest is essential for cell survival. The cell-cycle-arrest occurs via the down regulation of the cyclins that drive the main cyclin dependent kinase, CDK1/Cdc28. However, it was not clear how cells escape this potentially fatal arrest. Here we show that prior to the restoration of CDK1/Cdc28 cyclins, a non-canonical CDK, Pho85, initiates a cascade to restart the cell cycle. We demonstrate that following stress, Pho85 phosphorylates the Sch9 kinase, which in turn directly phosphorylates the transcriptional inhibitor Whi5, the yeast analog of RB1/retinoblastoma, and a CDK1 target. This promotes Whi5 translocation from the nucleus, and the release of the stress-induced arrest at G1 phase. In addition, we find that in parallel with Pho85, CDK1/Cdc28 also plays a role in the control of Whi5. Together, these findings provide insights into how cells re-enter the cell cycle during recovery from stress and reveal that a non-canonical CDK and cyclin takes on essential roles and acts via a pathway that functions in parallel with CDK1/Cdc28.

molecular biology↗

bioRxiv2023

Recruitment of the SNX17-Retriever recycling pathway regulates synaptic function and plasticity.

Trafficking of cell-surface proteins from endosomes to the plasma membrane is a key mechanism to regulate synaptic function. In non-neuronal cells, proteins recycle to the plasma membrane either via the SNX27-Retromer-WASH pathway, or via the recently discovered SNX17-Retriever-CCC-WASH pathway. While SNX27 is responsible for the recycling of key neuronal receptors, the roles of SNX17 in neurons are less understood. Here, using cultured hippocampal neurons, we demonstrate that the SNX17 pathway regulates synaptic function and plasticity. Disruption of this pathway results in a loss of excitatory synapses and prevents structural plasticity during chemical long-term potentiation (cLTP). cLTP drives SNX17 recruitment to synapses, where its roles are in part mediated by regulating surface expression of {beta}1-integrin. SNX17 recruitment relies on NMDAR activation, CamKII signaling, and requires binding to the Retriever and PI(3)P. Together, these findings provide molecular insights into the regulation of SNX17 at synapses, and define key roles for SNX17 in synaptic maintenance and in regulating enduring forms of synaptic plasticity.

cell biology↗

bioRxiv2021

Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons

Autophagy is a conserved, multi-step process of capturing proteolytic cargo in autophagosomes for lysosome degradation. The capacity to remove toxic proteins that accumulate in neurodegenerative disorders attests to the disease-modifying potential of the autophagy pathway. However, neurons respond only marginally to conventional methods for inducing autophagy, limiting efforts to develop therapeutic autophagy modulators for neurodegenerative diseases. The determinants underlying poor autophagy induction in neurons and the degree to which neurons and other cell types are differentially sensitive to autophagy stimuli are incompletely defined. Accordingly, we sampled nascent transcript synthesis and stabilities in fibroblasts, induced pluripotent stem cells (iPSCs) and iPSC-derived neurons (iNeurons), thereby uncovering a neuron-specific stability of transcripts encoding myotubularin-related phosphatase 5 (MTMR5). MTMR5 is an autophagy suppressor that acts with its binding partner, MTMR2, to dephosphorylate phosphoinositides critical for autophagy initiation and autophagosome maturation. We found that MTMR5 is necessary and sufficient to suppress autophagy in iNeurons and undifferentiated iPSCs. Using optical pulse labeling to visualize the turnover of endogenously-encoded proteins in live cells, we observed that knockdown of MTMR5 or MTMR2, but not MTMR9, significantly enhances neuronal degradation of TDP-43, an autophagy substrate implicated in several neurodegenerative diseases. Accordingly, our findings establish a regulatory mechanism of autophagy intrinsic to neurons and targetable for clearing disease-related proteins in a cell type-specific manner. In so doing, our results not only unravel novel aspects of neuronal biology and proteostasis, but also elucidate a strategy for modulating neuronal autophagy that could be of high therapeutic potential for multiple neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Lipid kinases VPS34 and PIKfyve coordinate a phosphoinositide cascade to regulate Retriever-mediated recycling on endosomes

Cell-surface receptors control how cells respond to their environment. Many cell-surface receptors recycle from endosomes to the plasma membrane via a recently discovered pathway, which includes sorting-nexin SNX17, Retriever, WASH and CCC complexes. Here we discover that PIKfyve and its upstream PI3-kinase VPS34 positively regulate this pathway. VPS34 produces PI3P, which is the substrate for PIKfyve to generate PI3,5P2. We show that PIKfyve controls recycling of cargoes including integrins, receptors that control cell migration. Furthermore, endogenous PIKfyve colocalizes with SNX17, Retriever, WASH and CCC complexes on endosomes. Importantly, PIKfyve inhibition causes a loss of Retriever and CCC from endosomes, and mutation of the lipid binding site on a CCC subunit impairs its endosomal localization and delays integrin recycling. In addition, we show that recruitment of SNX17 is an early step and requires VPS34. These discoveries suggest that VPS34 and PIKfyve coordinate an ordered pathway to regulate recycling from endosomes and suggest how PIKfyve functions in cell migration.

cell biology↗