Journal Club: Biochemistry, Cell Signaling, Oncology, and Neuroscience.

BIOCHEMISTRY: Heat shock transcription factor σ32 co-opts the signal recognition particle to regulate protein homeostasis in E. coli. Lim, B., et al. (Gross). PLoS Biol. 2013. 11(12):e1001735.

Stressful conditions that threaten protein stability, such as a rapid increase in temperature, lead to activation of the heat shock response (HSR), which features increased expression of proteins such as chaperones, which help other proteins fold.

In E. coli, the protein σ32 plays a critical role in the HSR by targeting RNA polymerase to HSR genes. Although many aspects of the regulation of σ32 have been determined, questions remain, including over the role of an essential piece of σ32 and how σ32 regulates intramembrane proteins.

In this report, members of the Gross lab answered both questions. They showed that the signal recognition particle and its receptor, previously known to direct proteins to the plasma membrane, regulate σ32. The signal recognition particle binds σ32 and leads it to the membrane, allowing for it to respond to membrane-associated triggers.

CELL SIGNALING: Cytoneme-mediated contact-dependent transport of the Drosophila decapentaplegic signaling protein. Roy, S., Huang, H., Liu, S., Kornberg, T.B. Science. 2014 Jan 2. [Epub ahead of print]

More than a decade ago, the Kornberg lab observed thin, lengthy projections of certain cells of the developing fruit fly wing that extended towards cells that produce factors regulating their development. They hypothesized that these projections, which they called cytonemes, were important for this regulation.  

In this paper, researchers presented data supporting this hypothesis, showing the transfer of an important signaling protein, Dpp, from the producing cell to the cytoneme and transport of Dpp back along the cytoneme. They further showed that several mutations that interfere with cytoneme development also result in disruptions in Dpp signaling.

Cytonemes have been observed in a variety of cell types in various species, and the authors suggest cytonemes may facilitate cell-cell communication in many settings.  

ONCOLOGY: Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Johnson, B.E., Mazor, T., et al. (Costello). Science. 2014. 343(6167):189-193.

Tumors show both genetic heterogeneity and evolution. Previous research has explored this in hematological malignancies and solid tumor metastases but not in local recurrence in the brain.

In this study, the authors compared the exomes (the expressed portion of the genome) of low-grade gliomas and their eventual recurrences. These included some tumors from patients treated with temozolomide (TMZ), a chemotherapeutic that is a known mutagen.

Surprisingly, they found that in nearly half of 23 cases, at least half of the mutations observed in the initial tumor were absent in the recurrence, suggesting that the originating cell of the recurrence originated early in the tumor’s evolution. They also found that the recurrences of patients treated with TMZ showed evidence of TMZ-induced mutagenesis and an alternative path to becoming high-grade tumors.

NEUROSCIENCE: Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. Skibinski, G., Nakamura, K., Cookson, M.R., Finkbeiner, S. J Neurosci. 2014. 34(2):418-433.

Most instances of Parkinson’s disease have no identifiable cause, but a minority are genetic, most commonly from mutations in leucine-rich repeat kinase 2 (LRRK2). The prevailing explanation for disease in these patients has been that mutant LRRK2 is toxic through its increased activity and aggregation into inclusion bodies.

In this paper, the authors challenged this hypothesis. They used a microscope that allows the tracking of thousands of individual neurons to monitor over time neurons induced from cells from human patients and rats with mutant LRRK2.

They found that inhibition of LRRK2 kinase activity appears to prevent toxicity to a degree that corresponds with the degree of reduction in the amount of LRRK2 protein present. They also unexpectedly found that reducing α-synuclein, another protein associated with Parkinson’s disease, decreased LRR2-mediated toxicity.