Mammalian microtubule P-body dynamics are mediated by nesprin-1

TY - JOUR

T1 - Mammalian microtubule P-body dynamics are mediated by nesprin-1

AU - Rajgor, Dipen

AU - Mellad, Jason A.

AU - Soong, Daniel

AU - Rattner, Jerome B.

AU - Fritzler, Marvin J.

AU - Shanahan, Catherine M.

PY - 2014/5/26

Y1 - 2014/5/26

N2 - Nesprins are a multi-isomeric family of spectrinrepeat (SR) proteins, predominantly known as nuclear envelope scaffolds. However, isoforms that function beyond the nuclear envelope remain poorly examined. Here, we characterize p50(Nespl), a 50-kD isoform that localizes to processing bodies (PBs), where it acts as a microtubule-associated protein capable of linking mRNP complexes to microtubules. Overexpression of dominant-negative p50(Nespl) caused Rck/p54, but not GW182, displacement from microtubules, resulting in reduced PB movement and cross talk with stress granules (SGs). These cells disassembled canonical SGs induced by sodium arsenite, but not those induced by hydrogen peroxide, leading to cell death and revealing PB microtubule attachment is required for hydrogen peroxide-induced SG anti-apoptotic functions. Furthermore, p50(Nespl) was required for miRNA-mediated silencing and interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. These data identify p50(Nespl) as a multi-functional PB component and microtubule scaffold necessary for RNA granule dynamics and provides evidence for PB and SG micro-heterogeneity.

AB - Nesprins are a multi-isomeric family of spectrinrepeat (SR) proteins, predominantly known as nuclear envelope scaffolds. However, isoforms that function beyond the nuclear envelope remain poorly examined. Here, we characterize p50(Nespl), a 50-kD isoform that localizes to processing bodies (PBs), where it acts as a microtubule-associated protein capable of linking mRNP complexes to microtubules. Overexpression of dominant-negative p50(Nespl) caused Rck/p54, but not GW182, displacement from microtubules, resulting in reduced PB movement and cross talk with stress granules (SGs). These cells disassembled canonical SGs induced by sodium arsenite, but not those induced by hydrogen peroxide, leading to cell death and revealing PB microtubule attachment is required for hydrogen peroxide-induced SG anti-apoptotic functions. Furthermore, p50(Nespl) was required for miRNA-mediated silencing and interacted with core miRISC silencers Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner. These data identify p50(Nespl) as a multi-functional PB component and microtubule scaffold necessary for RNA granule dynamics and provides evidence for PB and SG micro-heterogeneity.

KW - CYTOPLASMIC PROCESSING BODIES

KW - NUCLEAR-MEMBRANE PROTEIN

KW - STRESS GRANULES

KW - SPECTRIN-REPEAT

KW - MESSENGER-RNAS

KW - LINC COMPLEX

KW - ENVELOPE

KW - MUSCLE

KW - GENE

KW - IDENTIFICATION

U2 - 10.1083/jcb.201306076

DO - 10.1083/jcb.201306076

M3 - Article

SN - 0021-9525

VL - 205

SP - 457

EP - 475

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 4

ER -