Biology subjects

Wong, S.-W.

Publications and source records attributed to Wong, S.-W..

3 recordsLinked to original sources

bioRxiv2025

Melanoregulin deficiency affects bone maintenance and lean body mass

ObjectivesStudies documented the association of melanoregulin (MREG), a cargo-sorting protein, with its binding partner, the autophagic protein, microtubule-associated protein 1 light chain 3B (LC3B) in macrophages which could affect bone physiology due to the importance of autophagy in osteoclast function. Herein we propose to test the hypothesis that MREG modulates bone remodeling. Therefore, we analyzed the Mregdsu/dsu mutant mice for bone mass, growth plate microarchitecture, and bone marrow-derived osteoclast function to understand how lack of MREG affects bone and mass at two different time points. MethodsMice femurs from wild type and MREG-/- male mice (on C57BL6)/J background) were harvested at 4 and 10 months and imaged by microcomputed tomography to assess bone mass parameters. Femurs were processed for histology by H&E and TRAP staining for assessment of osteoclast numbers. Primary bone marrow-derived macrophages from 3-week-old mice were harvested to assess osteoclast differentiation and function via TRAP, resorptive assay and Western Blot for osteoclast differentiation markers. In addition, a separate cohort of mice were analyzed via EchoMRI to characterize total lean vs. fat whole body mass. ResultsThere was a statistically significant difference in bone volume of 10-month old mice in wild type vs. MREG-/- with MREG mutation suggesting a preservative effect on phenotypical bone parameters as the mice age. A reduction in adipose tissue but an increase in osteoclast numbers was found histologically in MREG mutant femurs. Bone marrow-derived cells, however, showed reduced osteoclastic function in MREG-/-. The mutant mice presented a total lean mass significantly increased compared to wild type per EchoMRI. ConclusionsMREG deficiency seems to impact osteoclast numbers in vivo but not in vitro, although in vitro function was reduced. MREG deficiency favors lean mass preservation over fat accumulation in bones and body composition as mice age. This study provides the foundation for a more in-depth investigation of MREGs role in bone and systemic metabolism. It is possible that MREG can be a future target for new therapeutic modalities in inflammatory and metabolic bone diseases.

cell biology↗

bioRxiv2023

Manipulation of the nucleoscaffold potentiates cellular reprogramming kinetics

Somatic cell fate is an outcome set by the activities of specific transcription factors and the chromatin landscape and is maintained by gene silencing of alternate cell fates through physical interactions with the nuclear scaffold. Here, we evaluate the role of the nuclear scaffold as a guardian of cell fate in human fibroblasts by comparing the effects of transient loss (knockdown) and mutation (progeria) of functional Lamin A/C, a core component of the nuclear scaffold. We observed that Lamin A/C deficiency or mutation disrupts nuclear morphology, heterochromatin levels, and increases access to DNA in lamina-associated domains. Changes in Lamin A/C were also found to impact the mechanical properties of the nucleus when measured by a microfluidic cellular squeezing device. We also show that transient loss of Lamin A/C accelerates the kinetics of cellular reprogramming to pluripotency through opening of previously silenced heterochromatin domains while genetic mutation of Lamin A/C into progerin induces a senescent phenotype that inhibits the induction of reprogramming genes. Our results highlight the physical role of the nuclear scaffold in safeguarding cellular fate.

cell biology↗

bioRxiv2019

Non-canonical autophagy in dendritic cells restricts cross-presentation and anti-tumor immunity

Major Histocompatibility Complex I (MHC-I) molecules classically present peptides derived from endogenous antigens, but exogenous antigens can also gain access to the MHC-I machinery in dendritic cells (DCs), which can activate antigen-specific CD8+ T cells. This process, termed cross-presentation, can be triggered by the uptake of dying autologous cells, including tumor cells, by DCs. The molecular mechanisms that underlie efficient cross-presentation remain largely uncharacterized, and an improved understanding of these mechanisms might reveal novel strategies for anti-tumor therapies. Rubicon (RUBCN) is a molecule required for LC3-associated phagocytosis (LAP), but dispensable for canonical autophagy, and mice lacking this protein develop an autoimmune inflammatory pathology with age. Here, we demonstrate that Rubcn-deficient DCs have increased retention of engulfed cellular cargo in immature phagosomes resulting in increased phagosome-to-cytosol escape and antigen access to proteasome-mediated degradation. As a result, mice selectively lacking Rubcn in DCs mount stronger tumor antigen-specific CD8+ T cell responses and exhibit decreased tumor burden compared to wild type littermates. These findings identify LAP as a key regulator of cross-presentation and suggest that targeting RUBCN might represent a novel strategy for anti-tumor therapy.

immunology↗