Journal Club: Immunology, Developmental Biology, Cell Biology, and Neuroscience

Editor
Graduate Division

IMMUNOLOGY: A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity. Duong, B.H., et al. (Ma, A.). Immunity. 2015. 42(1):55-67.

The production of certain inflammatory molecules, including interleukin-1β (IL-1β), requires the activity of large protein complexes called inflammasomes. Aberrant activation of inflammasomes has been linked to several diseases in which the immune system acts against the body.

Here, Duong and colleagues add to the field’s growing understanding of how these inflammasomes are normally controlled. They show that the protein A20, already well known in immunology for its role as a negative regulator of an important signaling pathway, is required for normal regulation of a particular inflammasome.

In the absence of A20, macrophages exposed to LPS spontaneously activated the NLRP3 inflammasome. In A20-deficient macrophages there was increased ubiquitination of pro-IL-1β, leading to more of it being processed to its active form. The observed phenotype required RIPK3 but not MyD88.

DEVELOPMENTAL BIOLOGY: A dynamic Shh expression pattern, regulated by SHH and BMP signaling, coordinates fusion of primordia in the amniote face. Hu, D., et al., (Marcucio, R.S.). Development. 2015. 142(3):567-574.

Successful development of the skull is important for more than just having a pretty face. Problems with facial development can lead to disorders such as cleft palate that, if not treated, can cause great discomfort and serious health problems.

An important event in facial development is the fusion of three portions of the frontonasal process to form the primary palate. It is at this point that the faces of developing birds and mammals are most similar. In this study, the authors show how SHH and BMP signaling coordinate this fusion.

They found that SHH and BMP signaling act in series to coordinate an expanding wave of Shh expression. This dynamic Shh expression allows for appropriately controlled growth of the facial components that contribute to the primary palate.

CELL BIOLOGY: The Nck-interacting kinase NIK increases Arp2/3 complex activity by phosphorylating the Arp2 subunit. LeClaire, L.L., et al. (Barber, D.L.). J Cell Biol. 2015. 208(2):161-170.

Cell migration—as in that famous biology class video clip in which the macrophage chases down the bacterium—requires successful formation of branched actin filaments. The Arp2/3 complex is known to be essential for that process. It is also well known that members of the WASP and WAVE protein families play an important role in regulating Arp2/3.

Now, these authors report that an unrelated protein can also drive Arp2/3 activity. They observed that the kinase NIK directly phosphorylates the Arp2 subunit, increasing complex activity.  

Normally, epidermal growth factor can cause membrane protrusions and increased Arp2/3 activity. The researchers found that this effect depended on NIK, thus identifying a new link between the growth factor and cellular cytoskeleton dynamics.

NEUROSCIENCE: SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. Cho, S.H., et al. (Gan, L.). J Neurosci. 2015. 35(2):807-818. 

That’s right, more IL-1β, this time regarding its role in neurodegeneration.

There is a strong link between aging and many neurodegenerative diseases. There is also increased inflammation in the brain as it ages, driven by increased innate immune system activity. In this article, Cho and colleagues present evidence linking these two phenomena.

They begin by observing that there is less SIRT1 in microglia of old mice—immune cells resident in the brain. SIRT1 is a deacetylase that has previously been implicated as having anti-aging activity. They found that decreased SIRT1 led to changes in the methylation at the IL-1β promoter and to increased IL-1β transcription. Finally, they noted that IL-1β can in turn lead to heightened aging-associated or tau-mediated memory defects in mice.