MS4A4A is a member of the membrane-spanning, four domain family, subfamily A (MS4A) that includes CD20 (MS4A1), FcRβ (MS4A2) and Htm4 (MS4A3). Like the first three members of this family, transcription of MS4A4A appears to be limited to hematopoietic cells. To evaluate expression of the MS4A4A protein in hematopoietic cell lineages and subsets we generated monoclonal antibodies against extracellular epitopes for use in flow cytometry. In human peripheral blood we found that MS4A4A is expressed at the plasma membrane in monocytes but not in granulocytes or lymphocytes. In vitro differentiation of monocytes demonstrated that MS4A4A is expressed in immature but not activated dendritic cells, and in macrophages generated in the presence of interleukin-4 ('alternatively activated' or M2 macrophages) but not by interferon-γ and lipopolysaccharide ('classically' activated or M1 macrophages). MS4A4A was expressed in the U937 monocytic cell line only after differentiation. In normal bone marrow, MS4A4A was expressed in mature monocytes but was undetected, or detected at only a low level, in myeloid/monocytic precursors, as well as their malignant counterparts in patients with various subtypes of myeloid leukemia. Although MS4A4A was not expressed in healthy B lymphocytes, it was highly expressed in normal plasma cells, CD138+ cells from multiple myeloma patients, and bone marrow B cells from a patient with mantle cell lymphoma. These findings suggest immunotherapeutic potential for MS4A4A antibodies in targeting alternatively activated macrophages such as tumor-associated macrophages, and in the treatment of multiple myeloma and mantle cell lymphoma.

IRES-mediated translation of key cell fate regulating genes has been implicated in tumorigenesis. Concerted action of canonical eukaryotic initiation factors and IRES transacting factors (ITAFs) was shown to regulate cellular IRES mediated translation; however, the precise molecular mechanism of ribosome recruitment to cellular IRESes remains unclear. Here we show that the X-linked inhibitor of apoptosis (XIAP) IRES operates in an evolutionary conserved viral like mode and the structural integrity, particularly in the vicinity of AUG, is critical for ribosome recruitment. The binding of eIF3 together with PABP potentiates ribosome recruitment to the IRES. Our data support the model in which eIF3 binds directly to the XIAP IRES RNA in a structure-dependent manner and acts as a scaffold for IRES RNA, PABP and the 40S ribosome.

Internal ribosome entry sites (IRESs) are cis-acting RNA elements capable of recruiting ribosomes and initiating translation on an internal portion of an mRNA. This is divergent from canonical eukaryotic translation initiation, where the 5' cap is recognized by initiation factors (IFs) that recruit the ribosome to initiate translation of the encoded peptide. All known IRESs are capable of initiating translation in a cap-independent manner, and are therefore not constrained by the absence or presence of a 5' mG cap. In addition to being cap-independent, IRES-mediated translation often uses only a subset of IFs allowing them to function independently of canonical initiation. The ability to function independently of the canonical translation initiation pathway allows IRESs to mediate gene expression when cap-dependent translation has been inhibited. Recent reports of viral IRESs capable of initiating translation across taxonomic domains (Eukarya and Bacteria) have sparked interest in designing gene expression systems compatible with multiple organisms. The ability to drive translation independent of cellular context using a common mechanism would have a wide range of applications ranging from agriculture biotechnology to the development of antiviral drugs. Here we discuss IRES-mediated translation and critically compare the available mechanistic and structural information. A particular focus will be on IRES-meditated translation across domains of life (viral and cellular IRESs) , IRES bioengineering and the possibility of an evolutionary conserved translation initiation mechanism.

Figure 1. The fate and chores of parenting scientists as seen by their children.