Biology subjects

Lee, Y.-S.

Publications and source records attributed to Lee, Y.-S..

25 records · Page 2Linked to original sources

bioRxiv2020

βPix sequesters IDOL and prevents LDL receptor degradation through a β2AR-regulated signaling pathway in Alport Syndrome

Alport syndrome (AS) is a rare disease of the glomerular basement membrane type IV collagen causing progressive renal failure. We reported increased accumulation of low-density lipoprotein (LDL) receptor (LDLR) and subsequent LDL cholesterol (LDL-C) uptake in renal tubular epithelial cells (TEC) in Alport mice, but the mechanisms regulating LDLR stability and function remain unknown. Here, we show that a selective {beta}2-Adrenoceptor ({beta}2AR) agonist, salbutamol, decreased LDLR levels and LDL-C uptake in Alport kidneys accompanied with reduced albuminuria and improved cardiac systolic and diastolic function. Similarly, salbutamol decreased LDL-C uptake in HK2 and HEK293 human renal epithelial cell lines, in smooth muscle cells from an X-linked hereditary nephropathy dog model (a large animal model of AS), and in TECs differentiated from AS patient-derived iPSCs. We show that the Rac1/Cdc42 guanine nucleotide exchange factor {beta}1Pix blocked {beta}2AR-induced LDLR degradation and, hence, increased LDL-C uptake. {beta}1Pix also abrogated ubiquitination and degradation of LDLR induced by the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase that promotes lysosomal LDLR ubiquitination and degradation. We identify a multimolecular complex comprised of {beta}Pix, IDOL, and LDLR and demonstrate that {beta}Pix counteracts {beta}2AR-mediated LDLR degradation by sequestering IDOL. Our findings show {beta}Pix acts as a significant post-transcriptional regulator of IDOL-mediated LDLR degradation and identify {beta}2AR activation as a potential treatment for Alport pathology.

molecular biology↗

bioRxiv2020

Social isolation impairs the prefrontal- nucleus accumbens circuit subserving social recognition in mice

The medial prefrontal cortex (mPFC) plays important roles in social behaviors, but it is not clear how early social experiences affect the mPFC and its subcortical circuit. We report that mice singly housed for 8 weeks immediately after weaning (SH mice) show a deficit in social recognition, even after 4 weeks of re-socialization. In SH mice, prefrontal infralimbic (IL) neurons projecting to the shell region of nucleus accumbens (NAcSh) showed decreased excitability compared to normally group housed (GH) mice. Furthermore, NAcSh-projecting IL neurons were activated when the mice encountered a familiar conspecific, which was not shown in SH mice. Chemogenetic inhibition of NAcSh-projecting IL neurons in normal mice selectively impaired social recognition without affecting social interaction, whereas activation of these neurons reversed social recognition deficit in SH mice. Therefore, mPFC IL-NAcSh projection is a novel brain circuit affected by early social experience; its activation is required for the social recognition.

neuroscience↗

bioRxiv2020

A transposon surveillance mechanism that safeguards plant male fertility during stress

Although plants are able to withstand a range of environmental conditions, spikes in ambient temperature can impact plant fertility causing reductions in seed yield and significant economic losses1,2. Therefore, understanding the precise molecular mechanisms that underpin plant fertility under environmental constraints is critical to safeguard future food production3. Here, we identified two Argonaute-like proteins whose activities are required to sustain male fertility in maize plants under high temperatures. We found that MALE-ASSOCIATED ARGONAUTE 1 and 2 (MAGO1 and MAGO2) associate with temperature-induced phased secondary small RNAs in pre-meiotic anthers and are essential to control the activity of retrotransposons in male meiocyte initials. Biochemical and structural analyses revealed how MAGO2 activity and its interaction with retrotransposon RNA targets are modulated through the dynamic phosphorylation of a set of highly conserved surface-located serine residues. Our results demonstrate that an Argonaute-dependent RNA-guided surveillance mechanism is critical in plants to sustain male fertility under environmentally constrained conditions by controlling the mutagenic activity of transposons in male germ cells.

plant biology↗

bioRxiv2020

Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network

Emotional memory processing, such as fear memory, engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network is largely unknown. Here, we illustrate a novel mechanism by which synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Firstly, we generated PC-specific STAT3 knockout (STAT3PKO) mice. Transcriptome analyses revealed that STAT3 deletion results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber to PC synapses was larger in STAT3PKO mice than in wild-type littermates. Conditioning at the parallel fiber induced long-term depression of parallel fiber-PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in wild-type littermates. Interestingly, STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory processing.

neuroscience↗

bioRxiv2020

Kv1.2 contributes to pattern separation by regulating the hippocampal CA3 neuronal ensemble size

Kv1.2 expression in rodent CA3 pyramidal cells (CA3-PC) is polarized to distal apical dendrites, and regulate the synaptic responses to perforant pathway (PP) inputs. Accordingly, Kv1.2 haploinsufficiency (Kcna2+/-) in CA3-PCs, but not Kv1.1 (Kcna1+/-), lowered the threshold for long-term potentiation at PP-CA3 synapses. The Kcna2+/- mice, but not Kcna1+/-, displayed impairments in contextual fear discrimination task. The size and overlap of CA3 ensembles activated by the first visits to slightly different contexts were not different between wildtype and Kcna2+/- mice, but these ensemble parameters diverged over training days between genotypes, suggesting abnormal plastic changes in the CA3 network of Kcna2+/- mice. Eventually, the Kcna2+/- mice exhibited larger ensemble size and overlap upon retrieval of two contexts, compared to wildtype or Kcna1+/- mice. These results suggest that Kv1.2 subunits prevent promiscuous plastic changes at PP-CA3 synapses, and contribute to sparse representation of memories and pattern separation in the CA3 network.

neuroscience↗

bioRxiv2019

Mul1 suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc

Activation of the Nlrp3 inflammasome consisting of three major components, Nlrp3, Asc, and pro-caspase-1, results in the activation of caspase-1 and subsequent proteolytic cleavage of pro-IL-1{beta} and pro-IL-18. To avoid excessive inflammatory response, the Nlrp3 inflammasome has to be precisely controlled. In this study, we show that the mouse mitochondrial E3 ubiquitin protein ligase (Mul1) suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc. In J774A.1 cells, Mul1 overexpression attenuated Nlrp3 activation, whereas Mul1 knockdown augmented Nlrp3 activation in terms of IL-1{beta} secretion and cleavage of pro-caspase-1 and pro-IL-1{beta}. Mul1 interacted with Asc, and ubiquitinated it at K21, K22, K26, and K55 residues, in a K48-linked manner, leading to proteasomal degradation. Convincingly, Mul1-mediated suppression of Nlrp3 activation was inhibited by K21R-, K22R-, K26R-, K52R-Asc mutants in RAW264.7 cells, when compared with the wild-type Asc. Furthermore, Aim2 inflammasome activation was also inhibited by Mul1 in the wild-type Asc-, but not in mutant Asc-expressing RAW264.7 cells. Taken together, these data suggest that Mul1 suppresses Nlrp3 inflammasome activation, through Asc ubiquitination and degradation.

immunology↗

bioRxiv2018

Unique unfoldase/aggregase activity of a molecular chaperone that dysregulates a translational elongation factor

The various chaperone activities of heat shock proteins contribute to ensuring cellular proteostasis. Here, we demonstrate the non-canonical unfoldase activity as an inherent functionality of the prokaryotic molecular chaperone Hsp33. The holding-inactive, reduced form of Hsp33 (RHsp33) strongly bound to the translational elongation factor, EF-Tu, and catalyzed the EF-Tu aggregation via evoking its aberrant folding, resulting in its susceptibility to proteolytic degradation by Lon. This interaction was critically mediated by the redox-switch domain of RHsp33 and the guanine nucleotide-binding domain of EF-Tu. The RHsp33-induced in vivo aggregation of EF-Tu upon heat shock was evident in a Lon-deficient strain and inhibited cell growth. Unlike wild-type Escherichia coli, the strain lacking both Hsp33 and Lon showed a non-reduced level of EF-Tu and diminished capability of counteracting heat shock. These findings suggest that the unique unfoldase/aggregase activity of Hsp33 potentially involved in protein turnover confers a cellular survival advantage under heat-stressed conditions.

biochemistry↗