Improving antibody language models with native pairing.

Existing antibody language models are limited by their use of unpaired antibody sequence data. A recently published dataset of ∼1.6 × 106 natively paired human antibody sequences offers a unique opportunity to evaluate how antibody language models are improved by training with native pairs. We trained three baseline antibody language models (BALM), using natively paired (BALM-paired), randomly-paired (BALM-shuffled), or unpaired (BALM-unpaired) sequences from this dataset. To address the paucity of paired sequences, we additionally fine-tuned ESM (evolutionary scale modeling)-2 with natively paired antibody sequences (ft-ESM). We provide evidence that training with native pairs allows the model to learn immunologically relevant features that span the light and heavy chains, which cannot be simulated by training with random pairs. We additionally show that training with native pairs improves model performance on a variety of metrics, including the ability of the model to classify antibodies by pathogen specificity.

Deciphering functional roles and interplay between Beclin1 and Beclin2 in autophagosome formation and mitophagy.

The degradation of macromolecules and organelles by the process of autophagy is critical for cellular homeostasis and is often compromised during aging and disease. Beclin1 and Beclin2 are implicated in autophagy induction, and these homologs share a high degree of amino acid sequence similarity but have divergent N-terminal regions. Here, we investigated the functions of the Beclin homologs in regulating autophagy and mitophagy, a specialized form of autophagy that targets mitochondria. Both Beclin homologs contributed to autophagosome formation, but a mechanism of autophagosome formation independent of either Beclin homolog occurred in response to starvation or mitochondrial damage. Mitophagy was compromised only in Beclin1-deficient HeLa cells and mouse embryonic fibroblasts because of defective autophagosomal engulfment of mitochondria, and the function of Beclin1 in mitophagy required the phosphorylation of the conserved Ser15 residue by the kinase Ulk1. Mitochondria-ER-associated membranes (MAMs) are important sites of autophagosome formation during mitophagy, and Beclin1, but not Beclin2 or a Beclin1 mutant that could not be phosphorylated at Ser15, localized to MAMs during mitophagy. Our findings establish a regulatory role for Beclin1 in selective mitophagy by initiating autophagosome formation adjacent to mitochondria, a function facilitated by Ulk1-mediated phosphorylation of Ser15 in its distinct N-terminal region.