Journal Club: Structural Biology, Genetics & Autoimmunity, Cancer Biology, and Neuroscience

STRUCTURAL BIOLOGY: Structure of the TRPA1 ion channel suggests regulatory mechanisms. Paulsen, C.E., et al. (Julius, D.). Nature. 2015. Epub ahead of print. 

Various ion channels in sensory neurons play an important role in reacting to noxious chemicals and other painful stimuli. In addition, they can have side benefits; for example, the receptor TRPA1 lets us appreciate the bite of wasabi in our Japanese food.

However, TRPA1 also plays an important role in some neurogenic inflammation, and better understanding it could aid development of new treatments. Here, the Julius group has determined the structure of TRPA1 using single-particle electron cryo-microscopy, an alternative to traditional X-ray crystallography. 

Previous research found inositol hexakisphosphate is essential for channel function. This study reveals that it binds the channel as a stabilizing co-factor. The authors also found an unexpected transient receptor potential-like allosteric domain, which provides a potential mechanism for the receptor’s high sensitivity.

GENETICS & AUTOIMMUNITY: COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Watkin, L.B., Jessen, B., et al. (Orange, J.S. & Shum, A.K.). Nat Genet. 2015. Epub ahead of print.

Over the past decde, next-generation sequencing has made sequencing an entire genome ever easier and cheaper. Such whole genome sequencing, or the more focused exome sequencing, which looks just at the portion of the genome that encodes proteins, has allowed for the cause of a number of rare genetic syndromes to be determined.

Both the Shum group at UCSF and the Orange group at Baylor College of Medicine encountered several families with inherited autoimmunity syndromes of arthritis and lung disease. In collaboration, they found that all the families had mutations in the COPA gene.

The COPA gene encodes a protein important in intracellular transport, and the mutations in these families impair Golgi-to-ER transport and lead to increased ER stress. The exact mechanism by which this transport defect leads to this focused autoimmunity remains an important question.

CANCER BIOLOGY: Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Rivera, L.B. et al. (Bergers, G.). Cell Rep. 2015. Epub ahead of print.

Tumors do not simply blithely grow in the body, ignoring all around them. No, they actively secrete factors to bend the body to their bidding, such as by suppressing the immune response against them or promoting the growth of new blood vessels.

Treatments to prevent such new blood vessel growth, through blocking VEGF/VEGFR signaling, can be quite efficacious albeit usually only for a limited amount of time. In this paper, the authors report an important role for non-tumor cells in the case of resistance.

Using mouse models of breast cancer and pancreatic neuroendocrine cancer, the researchers show effective VEGF/VEGFR targeting requires the induction of the immune-stimulatory molecule CXCL14. In turn, resistance arises when the tumor cells begin activating the PI3K pathway in myeloid cells (a subset of white blood cells) within the tumor.

NEUROSCIENCE: Brain perfusion in polysubstance users: relationship to substance and tobacco use, cognition, and self-regulation. Murray, D.E. et al. (Meyerhoff, D.J.). Drug Alcohol Depend. 2015. 150:120-128.

Studying the human brain has proved to be challenging. However, the development of MRI-based tools to study brain perfusion is a useful tool to look for changes in the activity of different brain regions.

Previous studies have looked at changes in brain perfusion in those dependent on alcohol and those dependent on stimulants, such as cocaine, but only limited research as been done on polysubstance users (PSU)--that is, those dependent on both alcohol and stimulants. In this study, the authors have compared a PSU group with alcohol-dependent and non-alcohol-dependent individuals.

They did not observe consistently lower perfusion in PSU than the alcohol group, with both showing decreased perfusion to the brain reward/executive region, correlating with worse performance in certain cognitive assays. However, cigarette smoking had an additional detrimental effect that was greater in PSU than in alcohol-alone.