bims-fascar 2021-05-02 papers

J Mol Cell Biol. 2021 Apr 29. pii: mjab028. [Epub ahead of print]

Mechanisms and regulation underlying membraneless organelle plasticity control.

Hazrat Ismail, Xu Liu, Fengrui Yang, Junying Li, Ayesha Zahid, Zhen Dou, Xing Liu, Xuebiao Yao.

Evolution has enabled living cells to adopt their structural and functional complexity by organizing intricate cellular compartments, such as membrane-bound and membraneless organelles, for spatiotemporal catalysis of physiochemical reactions essential for cell plasticity control. Emerging evidence and view support the notion that membraneless organelles are built by multivalent interactions of biomolecules via phase separation and transition mechanisms. In healthy cells, dynamic chemical modifications regulate membraneless organelle plasticity, and reversible phase separation is essential for cell homeostasis. Emerging evidence revealed that aberrant phase separation results in numerous neurodegenerative disorders, cancer, and other diseases. In this review, we provide molecular underpinnings on (i) mechanistic understanding of phase separation, (ii) unifying structural and mechanistic principles that underlie this phenomenon, (iii) various mechanisms that are used by cells for the regulation of phase separation, and (iv) emerging therapeutic and other applications.

Keywords: biomolecular condensates; intrinsically disordered proteins; liquid‒liquid phase separation; membraneless organelles; post-translational modifications

DOI: https://doi.org/10.1093/jmcb/mjab028

J Cell Biol. 2021 Jun 07. pii: e202009154. [Epub ahead of print]220(6):

PLCγ1 promotes phase separation of T cell signaling components.

Longhui Zeng, Ivan Palaia, Anđela Šarić, Xiaolei Su.

The T cell receptor (TCR) pathway receives, processes, and amplifies the signal from pathogenic antigens to the activation of T cells. Although major components in this pathway have been identified, the knowledge on how individual components cooperate to effectively transduce signals remains limited. Phase separation emerges as a biophysical principle in organizing signaling molecules into liquid-like condensates. Here, we report that phospholipase Cγ1 (PLCγ1) promotes phase separation of LAT, a key adaptor protein in the TCR pathway. PLCγ1 directly cross-links LAT through its two SH2 domains. PLCγ1 also protects LAT from dephosphorylation by the phosphatase CD45 and promotes LAT-dependent ERK activation and SLP76 phosphorylation. Intriguingly, a nonmonotonic effect of PLCγ1 on LAT clustering was discovered. Computer simulations, based on patchy particles, revealed how the cluster size is regulated by protein compositions. Together, these results define a critical function of PLCγ1 in promoting phase separation of the LAT complex and TCR signal transduction.

DOI: https://doi.org/10.1083/jcb.202009154

Cells. 2021 Apr 08. pii: 848. [Epub ahead of print]10(4):

The F-Actin-Binding MPRIP Forms Phase-Separated Condensates and Associates with PI(4,5)P2 and Active RNA Polymerase II in the Cell Nucleus.

Can Balaban, Martin Sztacho, Michaela Blažíková, Pavel Hozák.

Here, we provide evidence for the presence of Myosin phosphatase rho-interacting protein (MPRIP), an F-actin-binding protein, in the cell nucleus. The MPRIP protein binds to Phosphatidylinositol 4,5-bisphosphate (PIP2) and localizes to the nuclear speckles and nuclear lipid islets which are known to be involved in transcription. We identified MPRIP as a component of RNA Polymerase II/Nuclear Myosin 1 complex and showed that MPRIP forms phase-separated condensates which are able to bind nuclear F-actin fibers. Notably, the fibrous MPRIP preserves its liquid-like properties and reforms the spherical shaped condensates when F-actin is disassembled. Moreover, we show that the phase separation of MPRIP is driven by its long intrinsically disordered region at the C-terminus. We propose that the PIP2/MPRIP association might contribute to the regulation of RNAPII transcription via phase separation and nuclear actin polymerization.

Keywords: MPRIP; PIP2; actin; nucleus; phase separation

DOI: https://doi.org/10.3390/cells10040848