Researchers discover how multiple RNA elements control MicroRNA biogenesis

In humans (as well as all other organisms) genes encode proteins, which in turn regulate all the different specific cellular functions of the body. The genetic information found in our DNA is first converted into messenger RNA (mRNA) by a process called transcription. The mRNA acts as a template as it is read by intracellular organelles called ribosomes, which then create (or translate) the appropriate protein from the correct amino acid components. (more…)

Researchers reveal the pathogenesis of Usher syndrome, a hereditary deafness disease

Hair cell stereocilia convert mechanical signals (sound waves) into electrical signals (the opening of ion channels depolarizes cells to form receptor potentials) when hearing occurs. The structure of stereocilia is maintained by tip-link densities formed by the cadherin family. In Usher Syndrome, a hereditary deafness disease, such an arrangement of the stereocilia is disordered. Prof. Mingjie Zhang has demonstrated in Cell Reports that a point mutation of Myo7a (Myosin VIIa) found in Usher syndrome patients leads to disruption of the hair cell tip-link protein complex formation through liquid-liquid phase separation. (more…)

HKUST researchers decodes the target binding mechanisms governing the WW domain-containing proteins involved in cell growth and polarity

Prof. Mingjie Zhang and his collaborators decoded the binding mechanisms governing the WW domain tandem-containing proteins. Their findings, published in eLife, reveal the recognition mechanisms of tandem WW domains with their peptide ligands which can serve as a guiding tool for functional studies of WW domain-containing proteins in the future. (more…)

Researchers reveal mechanism governing AMPAR synaptic targeting and clustering

Prof. Mingjie Zhang and his team have reported that stargazin uses its entire C-terminal tail bind PSD-95 (Postsynaptic density protein 95) via a specific and multivalent interaction mode. Their findings, published in Neuron, reveal the mechanism of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor synaptic trafficking and transmission at the neuronal synapses. (more…)

An iPSC model reveals the underlying mechanism of transcriptional and synaptic dysregulation in mental disorders

Prof. Mingjie Zhang and his collaborators Prof. Ming from the University of Pennsylvania have reported a DISC1 (Disrupted-in-schizophrenia 1) and ATF4 (Activating Transcription Factor 4) interaction in iPSC (induced pluripotent stem cell)-derived neurons with a DISC1 mutation. Their findings, published in Molecular Psychiatry, reveal the underlying mechanisms linking the genetic lesion and functional phenotypes of psychiatric disorders.

Many mental disorders, including schizophrenia, are neurodevelopmental disorders arising from genetic aberrations and transcriptional dysregulation. A rare frameshift mutation in DISC1, a genetic risk factor implicated in several psychiatric disorders, has been shown to exhibit aberrant gene expression and defective synaptic functions. However, how DISC1 regulates gene expression was remained unclear.

ATF4, a DISC binding partner, is found to be more abundant in the nucleus of DISC1 mutant human cortical neurons and regulates the expression of a collection of dysregulated genes involved in synaptic function. When overexpressed in control neurons, the phenotypes recapitulates the synaptic deficits seen in DISC1 mutant neurons, whereas heterozygous ATF4 knockout rescues the transcription and synaptic deficits in DISC1 mutant neurons.

The high-resolution atomic structure of DISC1-ATF4 complex has also revealed that mutation in DISC1 disrupts the normal DISC1-ATF4 interaction, resulting in excessive ATF4 binding to DNA targets and deregulated gene expression.

These findings identify the molecular and structural interactions between DISC1 and ATF4 underlying the transcription and synaptic dysregulation in an iPSC model of mental disorders and provide insight into the pathogenesis of psychiatric disorders.

Journal Reference:

Wang X, Ye F, Wen Z, Guo Z, Yu C, Huang WK, Rojas Ringeling F, Su Y, Zheng W, Zhou G, Christian KM, Song H, Zhang M, Ming GL. Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders. Mol Psychiatry. 2019 Aug 23. doi: 10.1038/s41380-019-0485-2.

New insights into membrane trafficking regulated by ER fusion protein

Prof. Yusong and his collaborators Prof. Hu Junjie from the Institute of Biophysics of the Chinese Academy of Sciences reported that the endoplasmic reticulum (ER) fusogen atlastin (ATL) was involved in regulating cargo mobility and COPII formation in the ER. Their finding, published in PNAS on June 25, provides important insight into the physiological role of the tubular ER network.

Deletion or mutation of ATL in mammalian cells results in long unbranched ER tubules indicative of a lack of fusion between tubules, and mutation of human ATL1 is linked to hereditary spastic paraplegia. Prof. Hu’s previous work demonstrated that ATL and its homologs mediate fusion of the ER, particularly the tubular network, but the specific physiological functions of the tubular ER networks remain unclear.

After folding and proper modification, cargo proteins exited the ER through COPII coated vesicles. Researchers found that in ATL-deleted cells, COPII formation was drastically reduced in the cell periphery, and ER export became defective.

While ER exit site initiation was not affected, many of the sites failed to recruit COPII subunits. Subsequently, in vitro vesicular release assay revealed that the efficiency of cargo packaging into COPII vesicles was significantly reduced in cells lacking ATLs.

Further studies found that cargo was less mobile in the ER in the absence of ATL. Interestingly, the cargo mobility and COPII formation could be restored by ATL R77A, which was capable of tethering, but not fusing, ER tubules.

These findings suggest that ATL-mediated membrane tethering plays a critical role in maintaining the necessary mobility of ER contents to allow efficient packaging of cargo proteins into COPII vesicles. It has been shown that membrane tension affects the mobility of membrane components. The activity of ATL, particularly in membrane tethering, may contribute to regulating membrane tension in the ER.

Journal Reference:

Niu L, Ma T, Yang F, Yan B, Tang X, Yin H, Wu Q, Huang Y, Yao ZP, Wang J, Guo Y, Hu J. Atlastin-mediated membrane tethering is critical for cargo mobility and exit from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14029-14038. doi: 10.1073/pnas.1908409116.

Dr. Zilong Wen’s laboratory has discovered metaphocytes, a new cell type involving in immune in zebrafish

Dr. Wen’s laboratory has recently identified a myeloid-like cell population in zebrafish epidermis. This newly identified myeloid-like cell population, designated as metaphocytes, are of ectodermal origin but shares high similarities with mesoderm-derived conventional macrophages in the skin.

HKUST researchers discover that Vps4 protein helps delay degradation of injured nerves

A research team consisting of scientists from the Hong Kong University of Science and Technology (HKUST), Chinese Academy of Sciences (CAS) and Jinan University discovered a new mechanism that could delay the degeneration of injured nerves, bringing new hope to the treatment of nerve damage and neurodegenerative diseases such as Parkinson and Amyotrophic Lateral Sclerosis (ALS).