CD137 is expressed on activated T cells and NK cells, among others, and is a potent co-stimulator of antitumor immune responses. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), and CD137L reverse signaling into APC enhances their activity. CD137-CD137L interactions as main driver of type 1, cell-mediated immune responses explains the puzzling observation that CD137 agonists which enhance antitumor immune responses also ameliorate autoimmune diseases. Upon co-stimulation by CD137, Th1 CD4 T cells together with Tc1 CD8 T cells and NK cells inhibit other T cell subsets, thereby promoting antitumor responses and mitigating non-type 1 auto-immune diseases.

HepaCAM (GlialCAM) is frequently deleted in carcinomas, and reintroduction of hepaCAM into transformed cell lines reduces cellular growth and induces senescence. Mutations in HEPACAM give rise to the neurodegenerative disease megalencephalic leukoencephalopathy with subcortical cysts (MLC) since mutated hepaCAM prevents shuttling of MLC1 protein to astrocytic junctions in the plasma membrane. Here we identify that hepaCAM associates with connexin 43, a main component of gap junctions, and enhances connexin 43 localization to the plasma membrane at cellular junctions. HepaCAM also increases the levels of connexin 43, not by enhancing its transcription but by stabilizing connexin 43 protein. In the absence of hepaCAM, connexin 43 undergoes a faster degradation via the lysosomal pathway while proteasomal degradation seems not to be involved. Mutations in hepaCAM that cause MLC, or neutralization of hepaCAM by antibodies disrupt its association with connexin 43 at cellular junctions. By discovering the requirement of hepaCAM for localizing connexin 43, a well-established tumor suppressor, to cellular junctions and stabilizing it there, this study suggests a mechanism by which deletion of hepaCAM may support tumor progression.

SummaryBioengineering of photoautotrophic microalgae into CO 2 scrubbers and producers of valueadded metabolites is an appealing approach in low-carbon economy. A strategy for microalgal bioengineering is to enhance the photosynthetic carbon assimilation through genetically modifying the photosynthetic pathways. The halotolerant microalgae Dunaliella posses an unique osmoregulatory mechanism, which accumulates intracellular glycerol in response to extracellular hyperosmotic stresses. In our study, the Calvin cycle enzyme sedoheptulose 1,7-bisphosphatase from Chlamydomonas reinhardtii (CrSBPase) was transformed into Dunaliella bardawil, and the transformant CrSBP showed improved photosynthetic performance along with increased total organic carbon content and the osmoticum glycerol production. The results demonstrate that the potential of photosynthetic microalgae as CO 2 removers could be enhanced through modifying the photosynthetic carbon reduction cycle, with glycerol as the carbon sink.

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Intracellular pathogens are subject to elimination by a cellular immune response, and were therefore under evolutionary pressure to develop mechanisms that allow them to inhibit especially this arm of immunity. CD137, a T cell costimulatory molecule, and its ligand, CD137 ligand (CD137L), which is expressed on antigen presenting cells (APC), are potent drivers of cellular cytotoxic immune responses. Here, we report that different viruses usurp a negative feedback mechanism for the CD137-CD137L system that weakens cellular immune responses. Latent membrane protein (LMP)-1 and Tax, oncogenes of Epstein-Barr virus (EBV), and human T-cell lymphotropic virus (HTLV)-1, respectively, induce the expression of CD137. CD137 is transferred by trogocytosis to CD137L-expressing APC, and the CD137-CD137L complex is internalized and degraded, resulting in a reduced CD137-mediated T cell costimulation and a weakened cellular immune response which may facilitate the escape of the virus from immune surveillance. These data identify the usurpation of a CD137-based negative feedback mechanism by intracellular pathogens that enables them to reduce T cell costimulation.