Supporting tumor suppression: The protein PTEN is a phosphatase and tumor suppressor whose activity is often decreased in human cancers. Thus, reactivating such a protein could potentially be an effective therapy against cancer. Lee et al. identified a ubiquitin E3 ligase (WWP1) as a PTEN-interacting protein that modifies PTEN and inhibits its tumor suppressive activity (see the Perspective by Parsons). Depletion of WWP1 increased dimerization and membrane recruitment of PTEN. A natural compound found to be a pharmacological inhibitor of WWP1 inhibited tumor growth in a mouse model of prostate cancer. Thus, reactivation of the tumor suppressor PTEN may provide a strategy for battling tumors. Science , this issue p. eaau0159 ; see also p. 633

Vaccines have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity and mortality, yet emerging variants challenge their effectiveness. The prevailing approach to updating vaccines targets the antibody response, operating under the presumption that it is the primary defense mechanism following vaccination or infection. This perspective, however, can overlook the role of T cells, particularly when antibody levels are low or absent. Here we show, through studies in mouse models lacking antibodies but maintaining functional B cells and lymphoid organs, that immunity conferred by prior infection or mRNA vaccination can protect against SARS-CoV-2 challenge independently of antibodies. Our findings, using three distinct models inclusive of a novel human/mouse ACE2 hybrid, highlight that CD8⁺ T cells are essential for combating severe infections, whereas CD4⁺ T cells contribute to managing milder cases, with interferon-γ having an important function in this antibody-independent defense. These findings highlight the importance of T cell responses in vaccine development, urging a broader perspective on protective immunity beyond just antibodies.

Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrate that it searches for targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient targeting requires balanced interactions with chromatin: fusing p53 with an exogenous intrinsically disordered region potentiates p53-mediated target gene activation at low concentrations, but leads to condensates at higher levels, derailing its search and downregulating transcription. Our findings highlight the role of disordered regions on factors search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus to dissect how its organization guides nuclear factors action.