Rejection and killing, without MPR

An interaction that gets things started he nuclear envelope clearly helps regulate eukaryotic DNA replication, but many of the molecular pieces of this process are still unknown. On page 177, Martins et al. describe a novel, direct interaction between the nuclear envelope and the genome, mediated by the inner nuclear membrane protein LAP2b and the nuclear matrix– associated protein HA95, that is required for the initiation of replication. Having cloned HA95 two years ago, the authors now find that it interacts with LAP2b through two distinct domains. Abolishing the HA95–LAP2b interaction leads to the proteasome-mediated breakdown of prereplication complex component Cdc6, and a block in replication initiation. The HA95– LAP2b interaction is not required for DNA replication elongation or nuclear envelope reassembly after mitosis. The results add to the growing list of functions for HA95, which is also required for normal nuclear envelope breakdown and chromatin condensation, and is believed to facilitate the export of unspliced viral RNA from the nucleus. In replication initiation, HA95 probably works by protecting the prereplication complex from degradation. Martins et al. propose that the global distribution of HA95 in the nucleus and its ability to bind multiple ligands may explain why it appears in several critical regulatory pathways. ᭿ T Disrupting the chromatin–nuclear envelope link (bottom) prevents DNA replication initiation. hether destroying a tumor or rejecting a transplanted organ, cytotoxic lymphocytes rely on proteases called granzymes to kill target cells, so the finding two years ago that the action of a granzyme requires the mannose-6-phosphate receptor (MPR) on a target cell raised hopes for developing new classes of anticancer and antirejection drugs. Now, on page 223, Trapani et al. demonstrate that this optimism was premature, since endocytosis through MPR is actually not required for granzyme-mediated cell killing in a variety of systems. W Cells lacking MPR still take up granzyme B. Seeking to extend previous work (Motyka et al., 2000. Cell. 103:491–500), the authors first used cells defective for dynamin-mediated endocytosis or lacking MPR to study the uptake and effect of granzyme B, the major cell-killing granzyme. In cells unable to endocytose MPR, granzyme B uptake still occurs, albeit at a reduced rate, and cell killing is only slightly decreased. In mouse models, alloreactive tumor cells grafted under the renal capsule are rejected whether or not the cells can internalize MPR. The data suggest that when MPR-mediated uptake is blocked, granzyme B can still …