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The C. elegans PTPN22 ortholog functions in diverse developmental processes

ABSTRACT: Non-receptor type protein tyrosine phosphatases (PTPNs) have been studied extensively in the context of the adaptive immune system, however, their roles beyond immunoregulation are less unexplored. Here we identify novel functions for the conserved C. elegans phosphatase, PTPN-22, establishing new links to worm molting, cell adhesion, and cytoskeletal regulation. Through a non-biased genetic screen, we found that loss of PTPN-22 phosphatase activity suppresses molting defects caused by loss-of-function mutations in the conserved NIMA-related kinases, NEKL-2 (human NEK8/9) and NEKL-3 (human NEK6/7), which act at the interface of membrane trafficking and actin regulation. To better understand the functions of PTPN-22 we carried out proximity labeling studies to identify candidate interactors of PTPN-22 during development. Through this approach we identified the CDC42 guanine-nucleotide exchange factor DNBP-1 (human DNMBP) as an in vivo partner of PTPN-22 and showed that loss of DNBP-1 also suppresses nekl-associated molting defects and partially co-localizes with PTPN-22 in the epidermis. Genetics analysis, co-localization studies, and proximity labeling also revealed roles for PTPN-22 in several epidermal adhesion complexes including C. elegans hemidesmosomes, suggesting that PTPN-22 plays a broad role in maintaining the structural integrity of tissues. Localization and proximity labeling also implicated PTPN-22 in functions connected to nucleocytoplasmic transport and mRNA regulation, particularly within the germline, as nearly one third of proteins identified by PTPN-22 proximity labeling are known P granule components. Collectively, our studies highlight the utility of combined genetic and proteomic approaches for identifying novel gene functions.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Caenorhabditis Elegans (ncbitaxon:6239)

SUBMITTER: David S. Fay

PROVIDER: MSV000095492 | MassIVE | Wed Jul 31 07:19:00 BST 2024

SECONDARY ACCESSION(S): PXD054444

REPOSITORIES: MassIVE

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Project description:Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that gene mutations that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons enhance survival during hypertonic stress. Enhanced survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, loss of ASH neuron function reduces protein damage in non-neuronal cells. Improved proteostasis capacity is due in part to upregulation of genes that play important roles in managing protein damage. We propose that inhibitory signaling from ASH neurons normally suppresses expression of genes required for non-neuronal cell proteostasis. Because all cells have the capacity to sense and respond to stressors, inhibitory neuronal signaling may be important for minimizing activation of cellular stress resistance and proteostasis pathways during short duration and less extreme stressors or stressors that can be avoided by behavioral changes. Neuronal regulation of systemic proteostasis allows the nervous system to monitor environmental variables and more effectively partition finite energy resources between different organismal processes. Our studies add to a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs. mRNA expression profiling of synchronized L4 stage wild-type N2 Bristol and VC1262 osm-9(ok1677) C. elegans strains under control (51mM NaCl) and hypertonic stress (200mM NaCl).

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The C. elegans PTPN22 ortholog functions in diverse developmental processes

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