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Biology subjects

Cerutti, G.

Publications and source records attributed to Cerutti, G..

At least 19 recordsLinked to original sources

APETALA2 controls seed growth by regulating outer integument mechanical identity during seed coat differentiation

Organ morphogenesis requires differentiating cells to acquire mechanical properties that precisely regulate growth. In Arabidopsis thaliana, seed size and shape are largely controlled by the outer integument of the seed coat, whose two layers develop distinct mechanical behaviors critical for growth regulation. Here, we show that the cell identity factor APETALA2 (AP2) both promotes and restricts seed growth by coordinating the post-fertilization differentiation of these layers into distinct seed coat tissues. AP2 drives layer-specific remodeling of cell wall composition, notably affecting pectin and xyloglucan, thereby establishing contrasting mechanical properties between the two layers. Unexpectedly, these changes in wall composition and mechanics do not alter mechanosensitive responses, revealing a surprising uncoupling between cell wall remodeling and mechanotransduction. Our findings identify AP2 as a key coordinator of tissue-specific mechanical differentiation during organ morphogenesis.

plant biology↗

Actin Counters Geometry to Guide Plant Cell Division

In multicellular organisms, cell division shapes tissue architecture, cell identity, and function. In walled organisms like plants, division plane orientation irreversibly defines tissue topology and is tightly regulated. While divisions often follow the shortest path enclosing cell volume, certain cells deviate, dividing perpendicular to the growth axis. Tissue-scale mechanical stress has been proposed to guide such orientation, but how these cues are integrated remains unclear. Here, we re-examine the role of the actin cytoskeleton in orienting cell division in Arabidopsis root epidermis. Combining cell biology, genetics, pharmacological treatments, 3D segmentation, and modelling, we show that actin is a central molecular actor required to establish cell division orientation against the geometrical rules, highlighting its role in integrating spatial information.

plant biology↗

HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene

Broadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition. HighlightsO_LIIsolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaques C_LIO_LICryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognition C_LIO_LIAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame two C_LIO_LIThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodies C_LIO_LIStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition mode C_LIO_LIPropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naive rhesus repertoire C_LIO_LIDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity C_LI

immunology↗

Water fluxes contribute to growth patterning in shoot meristems

In multicellular organisms, localized tissue outgrowth creates a new water sink thereby modifying hydraulic patterns at the organ level. These fluxes are often considered passive by-products of development and their patterning and potential contribution to morphogenesis remains largely unexplored. Here, we generated a complete map of cell volumetric growth and deformation across the shoot apex in Arabidopsis thaliana. Within the organ-meristem boundary, we found that a subpopulation of cells next to fast-growing cells experiences volumetric shrinkage. To understand this process, we used a vertex-based model integrating mechanics and hydraulics, informed by the measured growth rates. Organ outgrowth simulations revealed the emerging water fluxes and predicted water deficit with volume loss for a few cells at the boundary. Consistently, in planta, a water-soluble dye is preferentially allocated to fast-growing tissues and fails to enter the boundary domain. Analysis of intact meristems further validated our model by revealing cell shrinkage next to fast-growing cells in different contexts of tissue surface curvature and cell deformation. A molecular signature of water deficit at the boundary further confirmed our conclusion. Taken together, we propose a model where the differential sink strength of emerging organs prescribes the hydraulic patterns that define the boundary domain at the shoot apex.

plant biology↗

bHLH heterodimer complex variations shape meristems in Arabidopsis thaliana by affecting target gene specificity

The main regions of cell proliferation in plants are the root and shoot apical meristems during primary growth and the vascular cambia as lateral meristems during secondary thickening. A number of unique regulators have been described in each of these meristems, suggesting that these different meristems might have independently evolved dedicated transcriptional networks to balance cell proliferation. Here, we show that the basic Helix Loop Helix (bHLH) transcription factor complexes formed by TARGET OF MONOPTEROS5 (TMO5), LONESOME HIGHWAY (LHW) and their close homologs are broadly expressed throughout plant development and operate as general regulators of cell proliferation in all meristems. Yet, genetic and expression analyses indicate that these complexes have specific functions in distinct meristems mediated by heterodimer complex variations between members of the TMO5 and LHW subclades. We determine that this is primarily due to their expression domains limiting the possible combinations of heterodimer complexes within a certain meristem, and to a certain extent to the absence of some members in a given meristem. We further demonstrate target gene specificity for heterodimer complexes, suggesting that spatial differences in transcriptional responses through heterodimer diversification allow a common bHLH heterodimer complex module to contribute to the control of cell proliferation in multiple meristems.

developmental biology↗

Vaccine-elicitation of cross-group neutralizing protective antibodies to influenza A viruses

Current influenza vaccines predominantly induce immunity to the hypervariable viral hemagglutinin (HA) head, requiring frequent vaccine reformulation. Conversely, antigenic sites on the conserved HA stem are subdominant and harbor a supersite which is targeted by broadly neutralizing antibodies (bnAbs), making it a prime target for universal vaccines. Here, we show that co-immunization of two stem immunogens derived from influenza A group 1 and 2 HAs elicits cross-group protective immunity and neutralizing antibody responses in mice, ferrets, and nonhuman primates (NHPs). Immunized mice were protected from multiple group 1 and 2 viruses, and all animal models showed broad serum neutralizing activity. A bnAb isolated from an immunized NHP broadly neutralized and conferred protection from viruses including H5N1 and H7N9. Genetic and structural analyses revealed a remarkable convergent evolution between macaque and human bnAbs, illustrating the biophysical constraints for acquiring immunoglobulins with cross-group specificity. Co-immunization of stem immunogens elicits not only group-specific protective immunity, but also cross-group bnAb responses, and represents a step towards broadly protective influenza vaccines.

immunology↗

Structural basis for antibody resistance to SARS-CoV-2 omicron variant

The recently reported B.1.1.529 Omicron variant of SARS-CoV-2 includes 34 mutations in the spike protein relative to the Wuhan strain that initiated the COVID-19 pandemic, including 15 mutations in the receptor binding domain (RBD). Functional studies have shown omicron to substantially escape the activity of many SARS-CoV-2-neutralizing antibodies. Here we report a 3.1 [A] resolution cryo-electron microscopy (cryo-EM) structure of the Omicron spike protein ectodomain. The structure depicts a spike that is exclusively in the 1-RBD-up conformation with increased mobility and inter-protomer asymmetry. Many mutations cause steric clashes and/or altered interactions at antibody binding surfaces, whereas others mediate changes of the spike structure in local regions to interfere with antibody recognition. Overall, the structure of the omicron spike reveals how mutations alter its conformation and explains its extraordinary ability to evade neutralizing antibodies. HighlightsO_LISARS-CoV-2 omicron spike exclusively adopts 1-RBD-up conformation C_LIO_LIOmicron substitutions alter conformation and mobility of RBD C_LIO_LIA subset of omicron mutations change the local conformation of spike C_LIO_LIThe structure reveals the basis of antibody neutralization escape C_LI

immunology↗

Isolation and comparative analysis of antibodies that broadly neutralize sarbecoviruses

The devastation caused by SARS-CoV-2 has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses and thus its promise as an agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses, but also uncovered a new antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine. One sentence summaryA monoclonal antibody that neutralizes or binds all sarbecoviruses tested and represents a reproducible antibody class.

microbiology↗

A monoclonal antibody that neutralizes SARS-CoV-2 variants, SARS-CoV, and other sarbecoviruses

The repeated emergence of highly pathogenic human coronaviruses as well as their evolving variants highlight the need to develop potent and broad-spectrum antiviral therapeutics and vaccines. By screening monoclonal antibodies (mAbs) isolated from COVID-19-convalescent patients, we found one mAb, 2-36, with cross-neutralizing activity against SARS-CoV. We solved the cryo-EM structure of 2-36 in complex with SARS-CoV-2 or SARS-CoV spike, revealing a highly conserved epitope in the receptor-binding domain (RBD). Antibody 2-36 neutralized not only all current circulating SARS-CoV-2 variants and SARS-COV, but also a panel of bat and pangolin sarbecoviruses that can use human angiotensin-converting enzyme 2 (ACE2) as a receptor. We selected 2-36-escape viruses in vitro and confirmed that K378T in SARS-CoV-2 RBD led to viral resistance. Taken together, 2-36 represents a strategic reserve drug candidate for the prevention and treatment of possible diseases caused by pre-emergent SARS-related coronaviruses. Its epitope defines a promising target for the development of a pan-sarbecovirus vaccine.

microbiology↗

Neutralizing antibody 5-7 defines a distinct site of vulnerability in SARS-CoV-2 spike N-terminal domain

Antibodies that potently neutralize SARS-CoV-2 target mainly the receptor-binding domain or the N-terminal domain (NTD). Over a dozen potently neutralizing NTD-directed antibodies have been studied structurally, and all target a single antigenic supersite in NTD (site 1). Here we report the 3.7 [A] resolution cryo-EM structure of a potent NTD-directed neutralizing antibody 5-7, which recognizes a site distinct from other potently neutralizing antibodies, inserting a binding loop into an exposed hydrophobic pocket between the two sheets of the NTD {beta}-sandwich. Interestingly, this pocket has been previously identified as the binding site for hydrophobic molecules including heme metabolites, but we observe their presence to not substantially impede 5-7 recognition. Mirroring its distinctive binding, antibody 5-7 retains a distinctive neutralization potency with variants of concern (VOC). Overall, we reveal a hydrophobic pocket in NTD proposed for immune evasion can actually be used by the immune system for recognition. HighlightsO_LICryo-EM structure of neutralizing antibody 5-7 in complex with SARS CoV-2 spike C_LIO_LI5-7 recognizes NTD outside of the previously identified antigenic supersite C_LIO_LI5-7 binds to a site known to accommodate numerous hydrophobic ligands C_LIO_LIStructural basis of 5-7 neutralization tolerance to some variants of concern C_LI

immunology↗

A quantitative gibberellin signalling biosensor reveals a role for gibberellins in internode specification at the shoot apical meristem

Growth at the shoot apical meristem (SAM) is essential for shoot architecture construction. The phytohormones gibberellins (GA) play a pivotal role in coordinating plant growth, but their role in the SAM remains mostly unknown. Here, we developed a ratiometric GA signalling biosensor by engineering one of the DELLA proteins, to suppress its master regulatory function in GA transcriptional responses while preserving its degradation upon GA sensing. We demonstrate that this novel degradation-based biosensor accurately reports on cellular changes in GA levels and perception during development. We used this biosensor to map GA signalling activity in the SAM. We show that high GA signalling is found primarily in cells located between organ primordia that are the precursors of internodes. By gain- and loss-of-function approaches, we further demonstrate that GAs regulate cell division plane orientation to establish the typical cellular organisation of internodes, thus contributing to internode specification in the SAM.

plant biology↗

Assessment of deep learning algorithms for 3D instance segmentation of confocal image datasets

Segmenting three dimensional microscopy images is essential for understanding phenomena like morphogenesis, cell division, cellular growth and genetic expression patterns. Recently, deep learning (DL) pipelines have been developed which claim to provide high accuracy segmentation of cellular images and are increasingly considered as the state-of-the-art for image segmentation problems. However, it remains difficult to define their relative performances as the concurrent diversity and lack of uniform evaluation strategies makes it difficult to know how their results compare. In this paper, we first made an inventory of the available DL methods for 3 dimensional (3D) cell segmentation. We next implemented and quantitatively compared a number of representative DL pipelines, alongside a highly efficient non-DL method named MARS. The DL methods were trained on a common dataset of 3D cellular confocal microscopy images. Their segmentation accuracies were also tested in the presence of different image artifacts. A specific method for segmentation quality evaluation was adopted which isolates segmentation errors due to under/over segmentation. This is complemented with a 3D visualization strategy for interactive exploration of segmentation quality. Our analysis shows that the DL pipelines have different levels of accuracy. Two of them, which are end to end 3D and were originally designed for cell boundary detection, show high performance, and offer clear advantages in terms of adaptability to new data. Author summaryIn recent years a number of deep learning (DL) algorithms based on computational neural networks have been developed which claim to achieve high accuracy and automatic segmentation of 3D microscopy images. Although these algorithms have received considerable attention in the literature, it is difficult to evaluate their relative performances, while it remains unclear whether they really perform better than other, more classical segmentation methods. To clarify these issues, we performed a detailed, quantitative analysis of a number of representative DL pipelines for cell instance segmentation from 3D confocal microscopy image datasets. We developed a protocol for benchmarking the performances of such DL based segmentation pipelines using common training and test datasets, evaluation metrics and visualizations. Using this protocol, we evaluated and compared four different DL pipelines to identify their strengths and limitations. A high performance non-DL method was also included in the evaluation. We show that DL pipelines may show significant differences in their performances depending on their model architecture and pipeline components but overall show excellent adaptability to unseen data. We also show that our benchmarking protocol could be extended to a variety of segmentation pipelines and datasets.

bioinformatics↗

Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization

The relative resistance of SARS-CoV-2 variants B.1.1.7 and B.1.351 to antibody neutralization has been described recently. We now report that another emergent variant from Brazil, P.1, is not only refractory to multiple neutralizing monoclonal antibodies, but also more resistant to neutralization by convalescent plasma (3.4 fold) and vaccinee sera (3.8-4.8 fold). The cryo-electron microscopy structure of a soluble prefusion-stabilized spike reveals the P.1 trimer to adopt exclusively a conformation in which one of the receptor-binding domains is in the "up" position, with the functional impact of mutations appearing to arise from local changes instead of global conformational alterations. The P.1 variant threatens current antibody therapies but less so the protective efficacy of our vaccines.

microbiology↗

Structural Basis for Accommodation of Emerging B.1.351 and B.1.1.7 Variants by Two Potent SARS-CoV-2 Neutralizing Antibodies

Emerging SARS-CoV-2 strains, B.1.1.7 and B.1.351, from the UK and South Africa, respectively show decreased neutralization by monoclonal antibodies and convalescent or vaccinee sera raised against the original wild-type virus, and are thus of clinical concern. However, the neutralization potency of two antibodies, 1-57 and 2-7, which target the receptor-binding domain (RBD) of spike, was unaffected by these emerging strains. Here, we report cryo-EM structures of 1-57 and 2-7 in complex with spike, revealing each of these antibodies to utilize a distinct mechanism to bypass or accommodate RBD mutations. Notably, each antibody represented a response with recognition distinct from those of frequent antibody classes. Moreover, many epitope residues recognized by 1-57 and 2-7 were outside hotspots of evolutionary pressure for both ACE2 binding and neutralizing antibody escape. We suggest the therapeutic use of antibodies like 1-57 and 2-7, which target less prevalent epitopes, could ameliorate issues of monoclonal antibody escape.

biochemistry↗

Potent SARS-CoV-2 Neutralizing Antibodies Directed Against Spike N-Terminal Domain Target a Single Supersite

Numerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed all seven antibodies to target a common surface, bordered by glycans N17, N74, N122, and N149. This site - formed primarily by a mobile {beta}-hairpin and several flexible loops - was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies target a single supersite.

biochemistry↗

Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent SARS-CoV-2-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determined structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three utilized VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy chain N53I enhancing binding and light chain tyrosines recognizing F486RBD. Despite these similarities, class members bound both RBD-up and -down conformations of the spike, with a subset of antibodies utilizing elongated CDRH3s to recognize glycan N343 on a neighboring RBD - a quaternary interaction accommodated by an increase in RBD separation of up to 12 [A]. The VH1-2-antibody class thus utilizes modular recognition encoded by modular genetic elements to effect potent neutralization, with VH-gene component specifying recognition of RBD and CDRH3 component specifying quaternary interactions. HighlightsO_LIDetermine structures of VH1-2-derived antibodies 2-43, 2-15, and H4 in complex with SARS-CoV-2 spike C_LIO_LIDefine a multi-donor VH1-2-antibody class with modular components for RBD and quaternary recognition C_LIO_LIReveal structural basis of RBD-up and RBD-down recognition within the class C_LIO_LIShow somatic hypermutations and avidity to be critical for potency C_LIO_LIDelineate changes in spike conformation induced by CDRH3-mediated quaternary recognition C_LI

immunology↗

Paired heavy and light chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses

Understanding protective mechanisms of antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We discovered a new antibody, 910-30, that targets the SARS-CoV-2 ACE2 receptor binding site as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. We performed sequence and structural analyses to explore how antibody features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer revealed its binding interactions and ability to disassemble spike. Despite heavy chain sequence similarity, biophysical analyses of IGHV3-53/3-66 antibodies highlighted the importance of native heavy:light pairings for ACE2 binding competition and for SARS-CoV-2 neutralization. We defined paired heavy:light sequence signatures and determined antibody precursor prevalence to be ~1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These data reveal key structural and functional neutralization features in the IGHV3-53/3-66 public antibody class to accelerate antibody-based medical interventions against SARS-CoV-2. HighlightsO_LIA molecular study of IGHV3-53/3-66 public antibody responses reveals critical heavy and light chain features for potent neutralization C_LIO_LICryo-EM analyses detail the structure of a novel public antibody class member, antibody 910-30, in complex with SARS-CoV-2 spike trimer C_LIO_LICryo-EM data reveal that 910-30 can both bind assembled trimer and can disassemble the SARS-CoV-2 spike C_LIO_LISequence-structure-function signatures defined for IGHV3-53/3-66 class antibodies including both heavy and light chains C_LIO_LIIGHV3-53/3-66 class precursors have a prevalence of 1:44,000 B cells in healthy human antibody repertoires C_LI

immunology↗

A pH-dependent switch mediates conformational masking of SARS-CoV-2 spike

The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the ACE2 receptor and to facilitate virus entry. Antibodies can engage RBD but some, such as CR3022, fail to inhibit entry despite nanomolar spike affinity. Here we show the SARS-CoV-2 spike to have low unfolding enthalpy at serological pH and up to 10-times more unfolding enthalpy at endosomal pH, where we observe significantly reduced CR3022 affinity. Cryo-EM structures -at serological and endosomal pH- delineated spike recognition of up to three ACE2 molecules, revealing RBD to freely adopt the up conformation. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a locked all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning and spike shedding of antibodies like CR3022. An endosomal mechanism involving spike-conformational change can thus facilitate immune evasion from RBD- up-recognizing antibody. HighlightsO_LIReveal spike at serological pH to have only ~10% the unfolding enthalpy of a typical globular protein, explaining how antibodies like CR3022 can bind with avidity C_LIO_LIDefine an endosomal mechanism whereby spike binds ACE2, but sheds CR3022, enabling immune evasion from potentially neutralizing antibody C_LIO_LIDetermine cryo-EM structures of the SARS-CoV-2 spike along its endosomal entry pathway-at pH 5.5, 4.5, and 4.0, and in complexes with ACE2 receptor at pH 7.4 and 5.5 C_LIO_LIShow spike to exclusively adopt an all RBD-down conformation at the low pH of the late endosome-early lysosome C_LIO_LIReveal structural basis by which a switch domain mediates RBD position in response to pH C_LI

immunology↗