Research Highlights in 2016

Cytoplasmic male sterility (CMS) factors have long been known in some wild plants, and also in some domesticated species, where they are used to produce plants to be used as maternal parents, for example to breed hybrids that display hybrid vigor. Their origins have been mystifying, and now a study recently published in Cell Research helps understand how one widely-used rice CMS factor evolved.

A recent study makes the surprising observation that autophagosomes can still form in the absence of the core conjugation machinery. Furthermore, while such autophagosomes can fuse with lysosomes, their degradation is delayed, and this is associated with delayed destruction of the inner autophagosomal double membrane, highlighting a new role for proteins thought to act exclusively in the formation of autophagosomes in late stages of the autophagic itinerary within autolysosomes.

Cells and organisms adapt to mitochondrial dysfunction by activating the mitochondrial unfolded protein response (UPR^mt), which is regulated by mitochondrial-to-nuclear communication; and UPR^mt activation can also be transmitted between different cell types suggesting a role in tissue coordination. Shao and colleagues now identify a neuronal circuit and a secreted neuropeptide required for cell non-autonomous UPR^mt regulation.

Studying the immune response against infection with hepatitis viruses is hampered by the lack of suitable preclinical model systems. A recent publication in Science identifies the cytosolic adapter molecule MAVS as being responsible for species restriction of infection with hepatitis A virus as well as linking cytosolic immune sensing in infected hepatocytes with innate effector functions and protective adaptive immunity.

A recent paper published in Nature reports that the immunosuppressive activity of tumor-associated macrophages is regulated via PI3Kγ signaling. Small-molecule inhibitors targeting PI3Kγ stimulate T cell activity against tumor alone and add additional effects for clinically proven PD1 immunotherapy.

Despite major advances in understanding the genetics and epigenetics of acute myelogenous leukemia, there is still a great need to develop more specific and effective therapies. High throughput approaches involving either genetic approaches or small molecule inhibitor screens are beginning to identify promising new therapeutic targets.

Recent evidence indicates that codon optimality is a broad determinant of mRNA stability. A study by Radhakrishnan et al. in Cell raises the possibility that the conserved DEAD-box protein Dhh1 underlies the phenomenon.

A near-atomic resolution structure of a mammalian voltage-gated calcium channel (Ca_v) has been determined. This first fully-assembled Ca_v structure illuminates mechanisms of Ca_v properties and functions and ushers in a new era in Ca_v research and beyond.

Two recent studies reveal a crucial role for the cation channel TRPM2 in sensing warm temperatures, both in the thermoregulatory center of the brain and in the somatosensory system.

Ubiquitin chains assembled via the N-terminal methionine (Met1 or linear ubiquitin), conjugated by the linear ubiquitin chain assembly complex (LUBAC), participate in NF-κΒ-dependent inflammatory signaling and immune responses. A recent report in Cell finds that OTULIN, a deubiquitinase that selectively cleaves Met1-linked ubiquitin chains, is essential for restraining inflammation in vivo.

At odds with their normal counterparts, hepatocellular carcinoma cells efficiently utilize ketone bodies to proliferate despite serum deprivation. These findings, which have been recently published in Cell Research, identify a novel metabolic circuitry through which tumors successfully cope with adverse microenvironmental conditions.

A recent paper published in Nature demonstrates a multifaceted relation between enteric glial cells (EGC), intestinal epithelia, and ILC3, via the EGC release of neurotrophic factors, a structurally related group of ligands within the TGF-β superfamily of signaling molecules and IL-22 produced by ILC3.

Ryanodine Receptors are large ion channels responsible for the release of Ca²⁺ from the Endoplasmic and Sarcoplasmic Reticulum, a prerequisite for muscle contraction. Recent cryo-electron microscopy data have allowed a direct visualization of allosteric motions within these membrane protein giants.

In a recent paper published in Cell, Matheoud et al. demonstrated that, in response to cellular stress, self-antigens can be extracted from mitochondria via mitochondrial-derived vesicles and presented at the cell surface to trigger an immune response; this pathway, termed mitochondrial antigen presentation (MitAP), is repressed by PINK1 and Parkin. These findings implicate autoimmune mechanisms in Parkinson's disease.

Differences in mitochondrial structures determine the metabolic landscape of effector and memory T cell populations in vivo.

Astrocytes are emerging as essential regulators of brain metastasis progression. In a current issue of Nature, Chen et al. identify a novel mechanism of astrocyte-carcinoma interaction and exploit vulnerabilities therein to slow brain metastatic growth in pre-clinical models.

Elimination of misfolded proteins of the endoplasmic reticulum (ER) requires their retrotranslocation from the ER to the cytosol via membrane-bound ubiquitin ligase complexes. Baldridge and Rapoport now reconstitute a key step of retrotranslocation, demonstrating a protein conduit gated by ubiquitination.

Generation and growth of the blood vasculature network is a highly synchronized process, requiring coordinated efforts of endothelial cells and pericytes to maintain blood vessel integrity and regeneration. In a recent paper published in Cell Research, Yu et al. identified and characterized bipotent Procr-expressing vascular endothelial stem cells, which give rise to both endothelial cells and pericytes.

The tumor microenvironment is recognized as a critical regulator of cancer progression, and multiple roles are also emerging for the microenvironment in modulating response to therapeutic intervention. A recent study by Wang and colleagues identified IFN-γ as a central effector of CD8⁺ T cell-mediated regulation of glutathione and cysteine metabolism in fibroblasts, which consequently abrogates stromal-induced resistance through modulation of cisplatin intracellular content in ovarian cancer cells.

The loss of stem cells, through cell dysfunction or senescence, is thought to contribute to biological aging. Recently, Hongbo Zhang and colleagues have shown that activation of the mitochondrial unfolded protein response, a retrograde stress response, through administration with an NAD⁺-raising compound, can rejuvenate stem cells and extend lifespan in mice.