NEK7 (human, Q8TDX7) curation notes

Provenance note: Provider deep research for NEK7 was not available (Falcon returned
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file exists. This notes file is a manual literature synthesis that replaces it. Every claim
below is anchored to a cached publication in publications/ with a verbatim quote.

Identity and family

• NEK7 is a 302-aa NIMA-related serine/threonine kinase, closest paralog NEK6
  PMID:11701951.
• Almost the whole protein is the kinase domain; NEK6/NEK7 "have little noncatalytic sequence
  but bind to the carboxyl-terminal noncatalytic tail of Nercc1/Nek9" PMID:12840024.

Catalytic activity and its regulation (NEK9 -> NEK7 cascade)

• NEK9 (Nercc1) activates NEK7 in vitro PMID:12840024.
• NEK7 is intrinsically autoinhibited by Tyr97 ("Tyr-down"); NEK9 C-terminal binding releases it
  PMID:19941817.
  Note: in this paper NEK9 is the activator and NEK7 the activated kinase; NEK7 itself is not shown to activate anything.
• NEK9 binds the NEK7 C-lobe, induces back-to-back dimerization and trans-autophosphorylation
  PMID:26522158.
• First physiological substrate with mapped sites: EML4 Ser144/Ser146
  PMID:31409757.

Mitotic/centrosomal role (catalytic)

• Centrosome-enriched, microtubule-independent
  PMID:17101132.
• Required for centrosomal microtubule nucleation and spindle assembly
  PMID:17586473
  PMID:17586473.
• Activated in mitosis; inactive mutants/depletion give fragile spindles; spindle pole localisation
  PMID:19414596.
• Chromosome congression via EML4 phosphorylation PMID:31409757.
• Mouse knockout: late embryonic/early postnatal lethality, cytokinesis failure, polyploidy, cilia defects
  PMID:20473324.
• He et al. state spindle function requires catalytic activity
  PMID:26814970.

NLRP3 inflammasome licensing (non-catalytic, scaffold)

• Genetic screens in mouse identified NEK7 as essential for NLRP3 activation
  [PMID:26553871 title "...Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation"];
  PMID:26814970.
• Direct binding to NLRP3 LRR; kinase-dead NEK7 (K64M) rescues
  PMID:26642356
  PMID:26814970.
• Mutual exclusivity with mitosis
  PMID:26642356.
• Cryo-EM NLRP3-NEK7 structure; NEK7 bridges NLRP3 subunits; NEK9- and NLRP3-binding surfaces overlap
  PMID:31189953.
• Active disc structure contains ten NLRP3 + ten NEK7; NEK7 opens the inactive cage at the MTOC
  PMID:36442502
  PMID:36442502.
• LATS1/2 phosphorylation of NLRP3 at the MTOC promotes NEK7 binding PMID:39173637.
• HCMV US18 associates with NEK7 and NLRP3 PMID:40450990.

Species/context caveat

• In human myeloid cells (BLaER1, THP-1), NLRP3 can be activated independently of NEK7 via an
  IKKβ-dependent priming route; mouse macrophages rely predominantly on NEK7
  PMID:36384135
  PMID:36384135.
  Human NEK7 can still prime NLRP3 when expressed
  PMID:36384135.

Other

• ANKS3 binds NEK7 and keeps it cytoplasmic PMID:26188091.
• Large-scale interactome screens (HuRI PMID:32296183; Haenig et al. Y2H PMID:32814053; kinase AP-MS PMID:32707033)
  report many binary partners; individually uninformative for function.
• Telomerase RNAi screen (PMID:21531765) – abstract does not mention NEK7; full text not available.

Curation decisions summary

• Core MF 1: protein serine/threonine kinase activity (mitotic spindle assembly, centrosome/spindle pole).
• Core MF 2: non-catalytic activator of NLRP3 (GO:0140677 with has_input NLRP3) -> positive regulation
  of NLRP3 inflammasome complex assembly; NEK7 is a stoichiometric subunit of the active NLRP3 disc.
• Do not combine kinase activity with inflammasome licensing: catalytic activity is dispensable there.
• GO:0140677 IDA from PMID:19941817 appears inverted (that paper shows NEK9 activating NEK7).
• 74 generic protein binding rows: REMOVE, except NLRP3 IPI from PMID:26814970 -> MODIFY to GO:0140677.