bims-micpro 2026-07-12 papers

J Exp Bot. 2026 Jul 10. pii: erag220. [Epub ahead of print]

Exploring the functions of Ded1/DDX3 proteins in plants.

Isabel C Okeke, René Toribio, M Mar Castellano, Alfonso Muñoz.

DEAD-box RNA helicases of the Ded1/DDX3 sub-family are essential regulators of cellular proteostasis. The functions of these proteins have been extensively studied in mammals and yeast. In these organisms, Ded1/DDX3 proteins play key roles in both canonical and non-canonical translation initiation and translation-related processes. Moreover, they also participate in different processes related to RNA metabolism. Plant homologues, although less studied, have revealed both conserved and unique functions compared with other eukaryotes. Members of this sub-family in plants play important roles in plant defence by regulating translation initiation of upstream open reading frames associated with stem loops situated downstream of their start codons during immune activation, as well as in loading small RNAs into extracellular vesicles. Additionally, these proteins have been associated with abiotic stress adaptation and with non-sense-mediated RNA decay, although the functional relevance of the latter remains unclear. This review provides an overview of the current knowledge about the structure, biochemical, and biological functions of Ded1/DDX3 sub-family members in both plant and non-plant eukaryotes, highlighting the peculiarities of plant Ded1/DDX3 members, and the major gaps that remain in understanding this protein sub-family in plants.

Keywords: DDX3; DEAD-box helicases; Ded1; RNA secondary structure; protein synthesis; stress response

DOI: https://doi.org/10.1093/jxb/erag220

Cell Mol Life Sci. 2026 Jul 06.

The BmCPV-derived viral small peptide vsp1S4(-) suppresses viral replication by triggering apoptosis via the ROS-JNK signalling pathway.

Xialing Chen, Xiaoyan Du, Lixuan Li, Yao Yao, Qian Teng, Haoni Xue, Min Zhu, Xing Zhang, Chengliang Gong, Xiaolong Hu.

Viral antisense RNAs are generally considered noncoding. Here, we show that segment 4 of Bombyx mori cypovirus (BmCPV) encodes a 78-aa antisense-microprotein, vsp1S4(-), that triggers a host-restrictive reactive oxygen species (ROS)-c-Jun N-terminal kinase (JNK)-apoptosis axis. vsp1S4(-) localizes to mitochondria, induces superoxide release, and activates JNK signalling. Consequently, cells undergo caspase-3-dependent apoptosis and S-phase arrest, while the levels of the viral structural protein (VP7) and progeny virions are strongly suppressed. Pharmacologic interruption of either ROS with N-acetylcysteine (NAC) or JNK signalling with SP600125, a dominant-negative JNK effectively rescues VP7 expression and restores viral replication, confirming that vsp1S4(-)-elicited signalling shows antiviral activity. Thus, BmCPV autonomously limits its own propagation through an antisense-encoded peptide that weaponizes host mitochondrial ROS and JNK, representing a paradigm of programmed self-attenuation operating via antisense translation.

Keywords: Apoptosis; BmCPV; ROS-JNK pathway; Viral replication; vsp1S4(-)

DOI: https://doi.org/10.1007/s00018-026-06230-0

bioRxiv. 2026 Jun 29. pii: 2026.06.23.732949. [Epub ahead of print]

Neprilysin mediated cleavage of phospholamban dysregulates SERCA in heart failure.

Jacob D Cunningham, Taylor A Phillips, Alexis R Mazzenga, Kush N Nagrani, Tuan H Bui, Seby Edassery, David Y Barefield, Seth L Robia.

Background: Neprilysin (NEP) is a zinc-dependent metalloprotease targeted in heart failure therapy to prevent it degrading circulating cardioprotective vasoactive peptides. NEP can also cleave sarcolipin (SLN), the skeletal- and atrial muscle-specific micropeptide regulator of the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA). A direct pathophysiological role of NEP in ventricular muscle has not been established.
Methods: Proteomics and immunoblot analysis of human myocardial specimens were used to quantify NEP abundance in failing and non-failing hearts. Heterologous protein expression and biochemical binding assays assessed NEP-mediated cleavage of phospholamban (PLB) and its impact on PLB-SERCA interactions. Functional consequences of NEP expression or inhibition were evaluated in neonatal rat ventricular myocytes and in a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of heart failure.
Results: We observed increased NEP abundance in failing human myocardium relative to non-failing controls. We demonstrated that NEP cleaves phospholamban (PLB), disrupting PLB-SERCA interactions. Mutation of PLB (V49A), prevented NEP cleavage and preserved PLB-SERCA binding, indicating V49 is critical for NEP substrate recognition. In neonatal rat ventricular myocytes, NEP expression was associated with faster Ca 2+ transient decay kinetics and increased SR Ca 2+ load, consistent with reduced SERCA inhibition. Inhibition of NEP in a hiPSC-CM heart failure model attenuated the hypertrophic transcriptional responses and reversed Ca 2+ -transport dysregulation.
Conclusions: These findings implicate increased NEP expression in the sarcoplasmic reticulum of cardiomyocytes as previously unrecognized maladaptive consequence of heart failure contributing to cardiac dysfunction. In this novel pathophysiological mechanism, increased NEP results in PLB cleavage and loss of regulation of SERCA. While this may relieve SERCA inhibition and augment cellular Ca 2+ handling, loss of PLB chronically disrupts heart's dynamic response to adrenergic stress, changing heart rate, or other physiological challenges. The data provide new insight into the cardioprotective effects of pharmacological NEP inhibition in clinical practice, reveal a novel mechanism of action of neprilysin inhibition in cardiomyocytes and may help inform future therapeutic strategies for patients with heart failure.

DOI: https://doi.org/10.64898/2026.06.23.732949