Coronin 1 in Innate Immunity

The WD repeat containing family of coronin proteins is generally referred to as F‑actin‑interacting proteins. While in lower eukaryotes such as Dictyostelium discoideum, the single short coronin protein regulates several F‑actin dependent processes such as motility, phagocytosis and macropinocytosis, the function of any of the seven coronin isoforms in mammals is far less understood. This chapter describes the current knowledge on mammalian coronin 1 (coronin 1A), the closest homologue to Dictyostelium short coronin that is exclusively expressed in leukocytes. Recent work based on biochemical, molecular biological and genetic analysis suggest that coronin 1 has evolved a function that is quite different from the F‑actin regulatory function of Dictyostelium short coronin. Rather, mammalian coronin 1 is involved in the regulation of leukocyte specific signaling events

Novel proteasome inhibitors as potential drugs to combat tuberculosis

Mycobacterium tuberculosis is one of the most notorious killers worldwide. These pathogens have evolved to infect human beings in a so-called dormant form that is extremely difficult to treat. New work, however, suggests that mycobacterial proteasomes, multicomponent structures that protect the microbe from damaging effects of nitric oxide generated by the host, can be selectively and specifically blocked by small molecules

Migration and homeostasis of naive T cells depends on coronin 1-mediated prosurvival signals and not on coronin 1-dependent filamentous actin modulation

Coronins are WD repeat-containing proteins highly conserved in the eukaryotic kingdom implicated in the regulation of F-actin. Mammalian coronin 1, one of the most conserved isoforms expressed in leukocytes, regulates survival of T cells, which has been suggested to be due to its role in preventing F-actin–induced apoptosis. In this study, we come to a different conclusion. We show that coronin 1 does not modulate F-actin and that induction of F-actin failed to induce apoptosis. Instead, coronin 1 was required for providing prosurvival signals, in the absence of which T cells rapidly underwent apoptosis. These results argue against a role for coronin 1 in F-actin–mediated T cell apoptosis and establish coronin 1 as an essential regulator of the balance between prosurvival and proapoptotic signals in naive T cells

The MHC class II-associated invariant chain contains two endosomal targeting signals within its cytoplasmic tail

The oligomeric complex formed by major histocompatibility complex (MHC) class II alpha and beta chains and invariant chain (Ii) assembles in the endoplasmic reticulum and is then transported via the Golgi complex to compartments of the endocytic pathway. When Ii alone is expressed in CV1 cells it is sorted to endosomes. The Ii cytoplasmic tail has been found to be essential for targeting to these compartments. In order to characterize further the signals responsible for endosomal targeting, we have deleted various segments of the cytoplasmic tail. The Ii mutants were transiently expressed and the cellular location of the proteins was analyzed biochemically and morphologically. The cytoplasmic tail of Ii was found to contain two endosomal targeting sequences within its cytoplasmic tail; one targeting sequence was present within amino acid residues 12-29 and deletion of this segment revealed the presence of a second endosomal targeting sequence, located within the first 11 amino acid residues. The presence of a leucine-isoleucine pair at positions 7 and 8 within this sequence was foundto be essential for endosomal targeting. In addition, the presence of this L-I motif lead to accumulation of Ii molecules in large endosomal vacuoles containing lysosomal marker proteins. Both wild type Ii and Ii mutant molecules containing only one endosomal targeting sequence were rapidly internalized from the plasma membrane. When the Ii cytoplasmic tail was fused to the membrane-spanning region of neuraminidase, a resident plasma membrane protein, the resulting chimera (INA)was found in endocytic compartments containing lysosomal marker proteins. Thus the cytoplasmic tail of Ii is sufficient for targeting to the endocytic/lysosomal pathway

Immunity against extracellular pathogens

Summary: Eukaryotic cells live in a relatively comfortable equilibrium with a wide variety of microbes. However, while many of the cohabiting microorganisms are harmless or even beneficial to the eukaryotic host, a number of prokaryotes have evolved the capacity to invade and replicate within host cells, thereby becoming potentially pathogenic. To be able to cope with potential pathogens, most organisms have developed several host defense mechanisms. First, microbes can be internalized and destroyed by a number of cell types of an innate immune system in a rather aspecific manner. Second, more complex organisms possess additionally an adaptive immune system that is capable of eliminating hazardous microbes in a highly specific manner. This review describes recent progress in our understanding of how pathogens interact with cells of the immune system, resulting in activation of the immune system or, for certain microorganisms, in the evasion of host defense reaction